Carvedilol phosphate

ABSTRACT

The invention encompasses novel amorphous and crystalline forms of carvedilol phosphate, carvedilol hydrogen phosphate, and carvedilol dihydrogen phosphate as well as methods of making the novel amorphous and crystalline forms. Also disclosed are pharmaceutical compositions comprising the novel amorphous and crystalline forms and uses thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefits of U.S. Provisional PatentApplications Nos. 60/817,634, filed 28 Jun. 2006; 60/837,878, filed 14Aug. 2006; 60/843,818, filed 11 Sep. 2006; 60/845,632, filed 18 Sep.2006; 60/845,879, filed 19 Sep. 2006; 60/846,699, filed 21 Sep. 2006;60/847,587, filed 26 Sep. 2006; 60/848,514, filed 28 Sep. 2006;60/851,366, filed 12 Oct. 2006; 60/853,505, filed 19 Oct. 2006;60/857,716, filed 7 Nov. 2006; 60/859,764, filed 16 Nov. 2006;60/878,914, filed 4 Jan. 2007; 60/897,083, filed 23 Jan. 2007;60/899,815, filed 5 Feb. 2007; 60/903,696, filed 26 Feb. 2007;60/927,098, filed 30 Apr. 2007; 60/927,099, filed 30 Apr. 2007; thecontents of all of which are incorporated herein by reference.

FIELD OF THE INVENTION

The invention encompasses carvedilol phosphate and solid states thereof.

BACKGROUND OF THE INVENTION

Carvedilol,(±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol,is a nonselective β-adrenergic blocker with α₁-blocking activity.Carvedilol is a racemic mixture having the following structural formula:

Carvedilol is the active ingredient in COREG®, which is indicated forthe treatment of congestive heart failure and for the management ofhypertension. Since carvedilol is a multiple-action drug, itsbeta-blocking activity affects the response to certain nerve impulses inparts of the body. As a result, beta-blockers decrease the heart's needfor blood and oxygen by reducing its workload. Carvedilol is also knownto be a vasodilator resulting primarily from alpha-adrenoceptorblockade. The multiple actions of carvedilol are responsible for theantihypertensive efficacy of the drug and for its effectiveness inmanaging congestive heart failure.

U.S. Pat. No. 4,503,067 (“'067 patent”) discloses a class ofcarbazolyl-(4)-oxypropanolamine compounds, including carvedilol. See'067 patent, col. 1, 1. 15 to col. 2, 1. 3. The '067 patent alsodiscloses the conversion of the compounds to their pharmacologicallyacceptable salts, by reacting the compound with “an equivalent amount ofan inorganic or organic acid,” such as phosphoric acid. See id. at col.4,11. 23-29.

U.S. publication No. 2005/0240027 (“'027 publication”) and U.S.publication No. 2005/0277689 (“'689 publication”) each disclose thatcarvedilol has “relatively low solubility” (<1 μg/mL) in alkaline media,and that its solubility increases with decreasing pH, up to about 100μg/mL. See '027 publication, p. 1, 7; '689 publication, p. 1, 7. Thesepublications also disclose solid and crystalline forms of carvedilolsalts, as well as solvates thereof. See, e.g., '027 publication, p. 3,51; '689 publication, p. 5, 169.

The discovery of new salt forms of carvedilol is needed in order to havegreater aqueous solubility and also greater chemical stability.

Solid state physical properties of a pharmaceutical compound can beinfluenced by controlling the conditions under which the compound isobtained in solid form. Solid state physical properties include, forexample, the flowability of the milled solid. Flowability affects theease with which the material is handled during processing into apharmaceutical product. When particles of the powdered compound do notflow past each other easily, a formulation specialist must take thatfact into account in developing a tablet or capsule formulation, whichmay necessitate the use of glidants such as colloidal silicon dioxide,talc, starch or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound isits rate of dissolution in aqueous fluid. The rate of dissolution of anactive ingredient in a patient's stomach fluid can have therapeuticconsequences since it imposes an upper limit on the rate at which anorally-administered active ingredient can reach the patient'sbloodstream. The rate of dissolution is also a consideration informulating syrups, elixirs and other liquid medicaments. The solidstate form of a compound may also affect its behavior on compaction andits storage stability.

These practical physical characteristics are influenced by theconformation and orientation of molecules in the unit cell, whichdefines a particular polymorphic form of a substance. The polymorphicform may give rise to thermal behavior different from that of theamorphous material or another polymorphic form. Thermal behavior ismeasured in the laboratory by such techniques as capillary meltingpoint, thermogravimetric analysis (TGA) and differential scanningcalorimetric (DSC) and can be used to distinguish some polymorphic formsfrom others. A particular polymorphic form may also give rise todistinct spectroscopic properties that may be detectable by powder X-raycrystallography, solid state ¹³C NMR spectrometry or infraredspectrometry.

One of the most important physical properties of a pharmaceuticalcompound, which can form polymorphs or solvates, is its solubility inaqueous solution, particularly the solubility in gastric juices of apatient. Other important properties relate to the ease of processing theform into pharmaceutical dosages, as the tendency of a powdered orgranulated form to flow and the surface properties determine whethercrystals of the form will adhere to each other when compacted into atablet.

The discovery of new solid states of a pharmaceutically useful compoundprovides a new opportunity to improve the performance characteristics ofa pharmaceutical product. It enlarges the repertoire of materials that aformulation scientist has available for designing, for example, apharmaceutical dosage form of a drug with a targeted release profile orother desired characteristic.

SUMMARY OF THE INVENTION Carvedilol Phosphate

In one embodiment, the invention encompasses carvedilol phosphate in anamorphous form. The invention also encompasses pharmaceuticalcompositions comprising amorphous carvedilol phosphate as well asmethods of treatment using such pharmaceutical compositions. X-raydiffractogram is substantially shown in FIG. 1.

In another embodiment, the invention encompasses a process for preparingcarvedilol phosphate in an amorphous form comprising: (a) providing asolution of carvedilol, phosphoric acid, and ethanol; (b) optionallyadding water to the solution to accelerate precipitation of thecarvedilol phosphate; and (c) recovering the carvedilol phosphate inamorphous form.

Carvedilol Hydrogen Phosphate

In one embodiment, the invention encompasses a crystalline form ofcarvedilol hydrogen phosphate, referred to herein as Form G, andcharacterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 6.5, 9.7, 13.0, 16.0 and 17.8degrees two theta ±0.2 degrees two theta; a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about: 145.8, 141.7 and 110.8±0.2ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about: 43.8, 39.7 and 8.8±0.1 ppm; any five peaks selected fromthe following list of PXRD peaks at about: 6.5, 9.7, 13.0, 13.5, 16.0,17.8, 22.8 and 23.2±0.2 degrees two theta; X-ray powder diffractionreflections at about: 6.5, 9.7, 13.5, 16.0 and 17.8 degrees two theta±0.2 degrees two theta; X-ray powder diffraction reflections at about:6.5, 9.7, 16.0, 18.4 and 23.2 degrees two theta ±0.2 degrees two theta;X-ray diffractogram substantially shown in FIG. 2; the solid-state¹³C-NMR substantially shown in FIG. 3 or 3 a.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol hydrogen phosphate, referred to herein as Form H, andcharacterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 6.4, 6.6, 9.4, 14.5 and 15.4degrees two theta ±0.2 degrees two theta; X-ray powder diffractionreflections at about: 6.6, 9.7, 13.0, 13.8 and 15.6 degrees two theta±0.2 degrees two theta; any five peaks selected from the following listof PXRD peaks at about: 6.5, 6.8, 9.6, 13.0, 13.6, 15.6, 17.5 and28.7±0.2 degrees two theta; X-ray powder diffraction reflections atabout: 6.5, 9.6, 13.0, 13.6 and 18.7 degrees two theta ±0.2 degrees twotheta; X-ray powder diffraction reflections at about: 6.5, 9.6, 13.6,18.7 and 20.2 degrees two theta ±0.2 degrees two theta; a solid-state¹³C-NMR spectrum having chemical shift resonances at about: 146.3, 142.6and 139.1±0.2 ppm; and a solid-state ¹³C NMR spectrum having chemicalshift differences between the lowest ppm resonance in the chemical shiftarea of 100 to 180 ppm and another in the chemical shift area of 100 to180 ppm of about 34, 30.3 and 26.8±0.1 ppm; X-ray diffractogramsubstantially shown in FIG. 4 or 5; solid-state ¹³C-NMR substantiallyshown in FIG. 6 or 6 a.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol hydrogen phosphate, referred to herein as Form K, andcharacterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 6.3, 9.8, 12.7, 13.2 and 16.9degrees two theta ±0.2 degrees two theta; X-ray diffractogramsubstantially shown in FIG. 7; any five peaks selected from thefollowing list of PXRD peaks at about: 6.3, 9.8, 12.7, 13.2, 16.3, 16.9,18.3 and 19.0±0.2 degrees two theta;

X-ray powder diffraction reflections at about: 6.3, 9.8, 16.9, 18.3 and23.2 degrees two theta ±0.2 degrees two theta; X-ray powder diffractionreflections at about: 6.3, 9.8, 14.9, 20.1 and 28.2 degrees two theta±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form Q,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 6.2, 7.3, 14.5, 17.5 and 21.3degrees two theta ±0.2 degrees two theta; X-ray diffractogramsubstantially shown in FIG. 8.

In another embodiment, the invention encompasses an amorphous form ofcarvedilol hydrogen phosphate. This amorphous form is substantiallydepicted in XRD diffractograms shown in FIG. 9 or 10

The invention also encompasses pharmaceutical compositions comprisingthe crystalline forms and the amorphous form of carvedilol hydrogenphosphate as well as methods of treatment using such pharmaceuticalcompositions.

In another embodiment, the invention encompasses processes for preparingthe crystalline forms and the amorphous form of carvedilol hydrogenphosphate.

Carvedilol Dihydrogen Phosphate

In one embodiment, the invention encompasses a process for preparingcrystalline carvedilol dihydrogen phosphate Form I, characterized bydata selected from the group consisting of: X-ray powder diffractionreflections at about: 7.0, 8.0, 9.2, 11.4 and 16.0 degrees two theta±0.2 degrees two theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 154.5, 146.5, 139.7 and 122.1±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 50.7,42.7, 35.9 and 18.3±0.1 ppm, comprising: combining carvedilol,phosphoric acid and a solvent selected from the group consisting ofC₁-C₈ alcohols, C₅-C₁₀ aliphatic hydrocarbons, C₆₋₁₂ aromatichydrocarbons, C₃-C₇ ketones, C₄-C₈ ethers, C₃-C₇ esters and acetonitrileand precipitating carvedilol dihydrogen phosphate Form I from thereaction mixture. X-ray diffractogram substantially shown in FIG. 11;solid-state ¹³C-NMR substantially shown in FIG. 12.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form L,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 4.6, 7.5, 8.7, 11.6 and 15.6degrees two theta ±0.2 degrees two theta; a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about 156.6, 150.3 and 102.5±0.2ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 54.1 and 47.8 and 0.0±0.1 ppm; X-ray diffractogram shown inFIG. 13; solid-state ¹³C-NMR shown in FIGS. 14 and/or 14 a; any fivepeaks selected from the following list of PXRD peaks at about: 4.6, 7.5,8.7, 11.6 13.4, 15.6 and 19.4±0.2 degrees two theta; X-ray powderdiffraction reflections at about: 4.6, 7.5, 8.7, 11.6 and 15.0 degreestwo theta ±0.2 degrees two theta; X-ray powder diffraction reflectionsat about: 4.6, 7.5, 8.7, 15.0 and 22.9 degrees two theta ±0.2 degreestwo theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form L1,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 4.6, 8.7, 11.6, 14.6 and 15.3degrees two theta ±0.2 degrees two theta; a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about 156.6, 150.3 and 148.4±0.2ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 53.2, 46.9 and 45.0±0.1 ppm; X-ray diffractogramsubstantially shown in FIG. 15; solid-state ¹³C-NMR substantially shownin FIGS. 16 and/or 16 a; PXRD peaks at about: 4.6, 7.4, 8.7, 11.6 14.6,15.3 and 19.4±0.2 degrees two theta; PXRD peaks at about 4.6, 7.4, 8.7,13.6 and 15.3 degrees two theta ±0.2 degrees two theta; PXRD peaks atabout 4.6, 7.4, 8.7, 11.6 and 17.4; PXRD peaks at about 4.6, 7.4, 8.7,15.3 and 17.4 degrees two theta ±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form N,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 6.0, 6.9, 15.2, 16.3 and 17.4degrees two theta ±0.2 degrees two theta; a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about 154.4, 146.9 and 138.4±0.2ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 52.9, 45.4 and 36.9±0.1 ppm; a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about 154.4, 146.9, 138.4 and110.9±0.2 ppm; a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 52.9, 45.4, 36.9 and 9.4±0.1 ppm; X-ray diffractogramsubstantially shown in FIGS. 17 and 18; solid-state ¹³C-NMRsubstantially shown in FIGS. 19 and/or 19 a; X-ray powder diffractionreflections at about: 6.0, 6.9, 13.7 15.2 and 18.1 degrees two theta±0.2 degrees two theta; X-ray powder diffraction reflections at about:6.0, 6.9, 13.7, 15.2 and 17.4±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form O,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 6.1, 12.2, 12.9, 16.2 and 18.0degrees two theta ±0.2 degrees two theta; X-ray diffractogram shown inFIG. 20.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form P,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 5.3, 10.4, 16.8, 26.0 and 31.8degrees two theta ±0.2 degrees two theta; a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about 154.7, 146.6 and 122.2±0.2ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 54.7, 46.6 and 22.2±0.1 ppm; X-ray diffractogram shown inFIG. 21; solid-state ¹³C-NMR shown in FIGS. 22 and/or 22 a; any fivepeaks selected from the following list of PXRD peaks at about: 5.3,10.4, 14.5, 16.8, 17.8, 26.0 and 31.8±0.2 degrees two theta; X-raypowder diffraction reflections at about: 5.3, 10.4, 15.2, 17.8 and 22.5degrees two theta ±0.2 degrees two theta; Form P can also becharacterized by X-ray powder diffraction reflections at about: 5.3,14.5, 15.2, 16.8 and 17.3 degrees two theta ±0.2 degrees two theta; FormP can also be characterized by X-ray powder diffraction reflections atabout: 5.3, 10.4, 14.5, 15.2 and 17.8 degrees two theta ±0.2 degrees twotheta; Form P can also be characterized by X-ray powder diffractionreflections at about: 5.3, 14.5, 15.2, 17.8 and 20.1 degrees two theta±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form F,characterized by data selected from: X-ray powder diffractionreflections at about: 7.7, 8.7, 16.8 and 22.8 degrees two theta ±0.2degrees two theta; X-ray powder diffraction reflections at about: 7.6,8.6, 16.7 and 22.8 degrees two theta ±0.2 degrees two theta; X-raypowder diffraction reflections at about: 7.7, 8.7, 16.8, 22.8 and 26.5degrees two theta ±0.2 degrees two theta; X-ray powder diffractionreflections at about: 7.6, 8.6, 16.7, 22.8 and 26.5 degrees two theta±0.2 degrees two theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 149.8, 145.4 and 140.7±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 50.6,46.2 and 41.5±0.1 ppm; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 149.8, 145.4, 138.5 and 140.7±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 50.6,46.2, 39.3 and 41.5±0.1 ppm; X-ray diffractogram shown in FIG. 23 or 24;solid-state ¹³C-NMR shown in FIGS. 25 and/or 25 a; X-ray powderdiffraction reflections at about: 7.7, 8.7, 13.5, 15.2 and 22.9 degreestwo theta ±0.2 degrees two theta; X-ray powder diffraction reflectionsat about: 7.6, 8.6, 13.4, 15.1 and 22.8 degrees two theta ±0.2 degreestwo theta; X-ray powder diffraction reflections at about: 7.7, 13.5,15.2, 18.3 and 18.9 degrees two theta ±0.2 degrees two theta; X-raypowder diffraction reflections at about: 7.6, 13.4, 15.1, 18.2 and 18.8degrees two theta ±0.2 degrees two theta; X-ray powder diffractionreflections at about: 7.7, 13.5, 15.2, 17.2 and 21.5 degrees two theta±0.2 degrees two theta; X-ray powder diffraction reflections at about:7.6, 13.4, 15.1, 17.1 and 21.4 degrees two theta ±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form F1,characterized by X-ray powder diffraction reflections at about: 7.6,9.8, 10.9, 21.2 and 25.0 degrees two theta ±0.2 degrees two theta; asolid-state ¹³C-NMR spectrum having chemical shift resonances at about155.3, 145.3 and 127.7±0.2 ppm; and a solid-state ¹³C NMR spectrumhaving chemical shift differences between the lowest ppm resonance inthe chemical shift area of 100 to 180 ppm and another in the chemicalshift area of 100 to 180 ppm of about 52.6, 42.6 and 25±0.1 ppm; X-raydiffractogram shown in FIG. 26 or 27; solid-state ¹³C-NMR shown in FIGS.28 and/or 28 a; X-ray powder diffraction reflections at about: 7.6,10.9, 13.3, 15.2 and 18.8 degrees two theta ±0.2 degrees two theta;X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 15.2 and16.9±0.2 degrees two theta; X-ray powder diffraction reflections atabout: 7.6, 9.8, 10.9, 14.7, 15.2 and 22.8±0.2 degrees two theta; X-raypowder diffraction reflections at about: 7.6, 8.5, 9.8, 13.3 and15.2±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form R,characterized by X-ray powder diffraction reflections at about: 5.8,11.8, 16.8, 18.6 and 23.2 degrees two theta ±0.2 degrees two theta; asolid-state ¹³C-NMR spectrum having chemical shift resonances at about153.7, 147.9 and 122.8±0.2 ppm; and a solid-state ¹³C NMR spectrumhaving chemical shift differences between the lowest ppm resonance inthe chemical shift area of 100 to 180 ppm and another in the chemicalshift area of 100 to 180 ppm of about 51.0, 45.2 and 20.1±0.1 ppm; X-raydiffractogram shown in FIG. 29; solid-state ¹³C-NMR shown in FIGS. 30and/or 30 a; X-ray powder diffraction reflections at about: 5.8, 11.8,15.5, 16.2 and 18.6 degrees two theta ±0.2 degrees two theta; X-raypowder diffraction reflections at about: 5.8, 16.2, 18.6, 23.2 and 27.0degrees two theta ±0.2 degrees two theta; X-ray powder diffractionreflections at about: 5.8, 16.2, 16.8, 19.9 and 25.4 degrees two theta±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form Y,characterized by X-ray powder diffraction reflections at about: 7.7,7.9, 9.1, 16.6 and 19.5 degrees two theta ±0.2 degrees two theta; X-raypowder diffraction reflections at about: 7.7, 8.5, 16.6, 19.5 and 20.3degrees two theta; X-ray diffractogram as substantially shown in FIG.31.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form W,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 6.6, 9.7, 13.8, 15.7 and 17.1degrees two theta ±0.2 degrees two theta; X-ray diffractogram is shownin FIG. 32.

In another embodiment, the invention encompasses an essentiallyamorphous form of carvedilol dihydrogen phosphate characterized by dataselected from the group consisting of: a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about 154.6, 146.7 and 140.3±0.2ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 54.2, 46.3 and 39.9±0.1 ppm; solid-state ¹³C-NMR spectrumhaving broad chemical shift resonances at about 154.6, 146.7, 140.3 and100.4±0.2 ppm; and a solid-state ¹³C-NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 54.2, 46.3, 39.9 and 0.0±0.1 ppm; X-ray diffractogram assubstantially shown in FIG. 33; solid-state ¹³C-NMR spectrum assubstantially shown in FIGS. 34 and/or 34 a.

In another embodiment the present invention provides a crystalline formof Carvedilol phosphate salt, referred to herein as Form F2. Form F2 ischaracterized by an X-Ray powder diffraction pattern with peaks at about7.4, 7.9, 8.5, 8.9 and 11.1±0.2 degrees two theta. The Calculated X-raypowder diffraction pattern of Carvedilol phosphate salt Form F2 issubstantially depicted in FIG. 35. The structure was solved by directmethods for triclinic P-1 group with the unit cell parameters:a=13.281(3), b=14.315(3), c=16.406(4)Å, α=66.85(2), β=85.94(2)γ=65.44(4) [deg], and cell volume 2592.4(12)Å³.

The invention also encompasses pharmaceutical compositions comprisingthe crystalline forms and the amorphous form of carvedilol dihydrogenphosphate as well as methods of treatment using such pharmaceuticalcompositions.

In another embodiment, the invention encompasses processes for preparingthe crystalline forms and the amorphous form of carvedilol dihydrogenphosphate.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a PXRD for carvedilol phosphate amorphous form.

FIG. 2 is a powder X-ray diffractogram for carvedilol hydrogen phosphateForm G.

FIG. 3 illustrate a solid-state ¹³C-NMR spectrum of carvedilol hydrogenphosphate Form G.

FIG. 3 a illustrate a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form G in the chemical shift area of 100 to 180ppm.

FIGS. 4 and 5 are powder X-ray diffractograms for carvedilol hydrogenphosphate Form H.

FIG. 6 illustrate a solid-state ¹³C-NMR spectrum of carvedilol hydrogenphosphate Form H.

FIG. 6 a illustrate a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form H in the chemical shift area of 100 to 180ppm.

FIG. 7 is a powder X-ray diffractogram for carvedilol hydrogen phosphateForm K.

FIG. 8 is a powder X-ray diffractogram for carvedilol hydrogen phosphateForm Q.

FIG. 9 is a powder X-ray diffractogram for the amorphous form ofcarvedilol hydrogen phosphate (according to Example 12).

FIG. 10 is a powder X-ray diffractogram for the amorphous form ofcarvedilol hydrogen phosphate (according to Example 13).

FIG. 11 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form I.

FIG. 12 illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form I.

FIG. 13 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form L.

FIG. 14 illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form L.

FIG. 14 a illustrate a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form L in the chemical shift area of 100 to 180ppm.

FIG. 15 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form L1.

FIG. 16 illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form L1.

FIG. 16 a illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form L1 in the chemical shift area of 100 to 180ppm.

FIGS. 17 and 18 illustrate a characteristic powder X-ray diffractogramfor carvedilol dihydrogen phosphate Form N.

FIG. 19 illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form N.

FIG. 19 a illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form N in the chemical shift area of 100 to 180ppm.

FIG. 20 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form O.

FIG. 21 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form P.

FIG. 22 illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form P.

FIG. 22 a illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form P in the chemical shift area of 100 to 180ppm.

FIG. 23 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form F obtained in Example 49.

FIG. 24 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form F obtained in Example 50.

FIG. 25 illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form F.

FIG. 25 a illustrate a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form F in the chemical shift area of 100 to 180ppm.

FIG. 26 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form F1 obtained in Example 52.

FIG. 27 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form F1 obtained in Example 86.

FIG. 28 illustrate a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form F1.

FIG. 28 a illustrates a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form F1 in the chemical shift area of 100 to 180ppm.

FIG. 29 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form R.

FIG. 30 illustrate a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form R.

FIG. 30 a illustrate a solid-state ¹³C-NMR spectrum of carvediloldihydrogen phosphate Form R in the chemical shift area of 100 to 180ppm.

FIG. 31 illustrates a characteristic powder X-ray diffractogram forphosphate salt of carvedilol Form Y.

FIG. 32 illustrates a characteristic powder X-ray diffractogram forcarvedilol dihydrogen phosphate Form W.

FIG. 33 illustrates a characteristic powder X-ray diffractogram for theamorphous form of carvedilol dihydrogen phosphate.

FIG. 34 illustrates a solid-state ¹³C-NMR spectrum of the amorphous formof carvedilol dihydrogen phosphate.

FIG. 34 a illustrate a solid-state ¹³C-NMR spectrum of the amorphousform of carvedilol dihydrogen phosphate in the chemical shift area of100 to 180 ppm.

FIG. 35 illustrates a characteristic powder X-ray diffractogram for thecarvedilol hydrogen phosphate Form F2.

FIG. 36 is an SEM image of the Form I.

FIG. 37 is an SEM images of the Form IV.

FIG. 38 is a Microscope image of the Form I.

FIG. 39 illustrates the % Crystallinity of Form L.

FIG. 40 illustrates the % Crystallinity of Form L1.

FIG. 41 illustrates the % Crystallinity of Form I.

FIG. 42 is a Microscope image of the Form N.

FIG. 43 illustrates the % Crystallinity of Form N.

FIG. 44 is a Microscope image of the Form IV.

FIG. 45 is a Microscope image of Form F.

FIG. 46 illustrates the % Crystallinity of Form F.

FIG. 47 is a Microscope image of Form F1.

FIG. 48 illustrates the % Crystallinity of Form F1.

FIG. 49 is a Microscope image of Form R.

FIG. 50 illustrates the % crystallinity of R.

FIG. 51 is a Microscope image of Form Y.

FIG. 52 is an SEM images of amorphous form 1:1.

FIG. 53 is the % crystallinity of Form P.

DETAILED DESCRIPTION OF THE INVENTION

There is a need in the art for solid forms of carvedilol phosphate,carvedilol hydrogen phosphate, and carvedilol dihydrogen phosphate withincreased solubility over the carvedilol free base. Increased solubilityleads to improved bioavailability when the drug is administered to apatient, and thus allows for a reduction in the dosages required. Theinvention addresses this need by providing amorphous forms andcrystalline forms of carvedilol phosphate, carvedilol hydrogen phosphateand carvedilol dihydrogen phosphate, which are more readily soluble thancarvedilol free base. Also provided are processes for preparing theamorphous forms and crystalline forms of carvedilol phosphate,carvedilol hydrogen phosphate and carvedilol dihydrogen phosphate.

As used herein, unless otherwise defined, the term “carvedilolphosphate” refers to a tricarvedilol phosphate complex, in whichcarvedilol and phosphate are present in a molar ratio of about 3:1.

As used herein, the term “carvedilol hydrogen phosphate” refers to acarvedilol phosphate salt, in which carvedilol and phosphoric acid arepresent in a molar ratio of about 2:1.

As used herein, the term “carvedilol dihydrogen phosphate” refers to acarvedilol phosphate salt, in which carvedilol and phosphate are presentin a molar ratio of about 1:1.

“Therapeutically effective amount” means the amount of a crystallineform that, when administered to a patient for treating a disease orother undesirable medical condition, is sufficient to have a beneficialeffect with respect to that disease or condition. The “therapeuticallyeffective amount” may vary depending on the crystalline form, thedisease or condition and its severity, and the age, weight, etc., of thepatient to be treated. Determining the therapeutically effective amountof a given crystalline form is within the ordinary skill of the art andrequires no more than routine experimentation.

“Pharmaceutically acceptable” means a substance which is notbiologically or otherwise undesirable, i.e., the substance can beadministered to an individual without causing significant undesirableeffects.

As used herein, the term “water content” refers to the content of waterbased upon the Loss on Drying method (the “LOD” method) as described inUPS 29-NF 24, official Aug. 1, 2006, Physical Test and Determinations,(731) LOSS ON DRYING or in Pharmacopeial Forum, Vol. 24, No. 1, p. 5438(January-February 1998), the Karl Fisher assay for determining watercontent or thermogravimetric analysis (TGA). All percentages herein areby weight unless otherwise indicated. Those skilled in the art will alsounderstand that the term “dihydrate” when used in reference tocarvedilol dihydrogen phosphate describes carvedilol dihydrogenphosphate having a water content of between about 4.7-6.9% w/w. Thoseskilled in the art will also understand that the term “hemihydrate” whenused in reference to carvedilol dihydrogen phosphate describescarvedilol dihydrogen phosphate having a water content of about 1.7-2.0%w/w.

As used herein, the term “GC measurement of residual solvent” refers toan automatic headspace gas-chromatographic system.

As used herein, “solvate” is meant to include any crystalline form whichincorporates solvent in a level of more than about 1%.

Those skilled in the art will understand that the term “hemimethanolate”when used in reference to carvedilol dihydrogen phosphate describescarvedilol dihydrogen phosphate having a methanol content of betweenabout 2.7-3.2% w/w.

Those skilled in the art will understand that the term “hemiethanolate”when used in reference to carvedilol dihydrogen phosphate describescarvedilol dihydrogen phosphate having an ethanol content of betweenabout 4.4-4.7% w/w.

Those skilled in the art will understand that the term “isopropanolsolvate” when used in reference to carvedilol dihydrogen phosphatedescribes carvedilol dihydrogen phosphate having an isopropanol contentof between about 7.5-10.3% w/w.

Spray drying broadly refers to processes involving breaking up liquidmixtures into small droplets (atomization) and rapidly removing solventfrom the mixture. In a typical spray drying apparatus, there is a strongdriving force for evaporation of solvent from the droplets, which may beprovided by providing a drying gas. Spray drying processes and equipmentare described in Perry's Chemical Engineer's Handbook, pp. 20-54 to20-57 (6th ed. 1984) and Remington: The Science and Practice ofPharmacy, 19th ed., vol. 1, pg. 1627, which are herein incorporated byreference.

By way of non-limiting example only, the typical spray drying apparatuscomprises a drying chamber, atomizing means for atomizing asolvent-containing feed into the drying chamber, a source of drying gasthat flows into the drying chamber to remove solvent from theatomized-solvent-containing feed, an outlet for the products of drying,and product collection means located downstream of the drying chamber.Examples of such apparatuses include Niro Models PSD-1, PSD-2 and PSD-4(Niro A/S, Soeborg, Denmark). Typically, the product collection meansincludes a cyclone connected to the drying apparatus. In the cyclone,the particles produced during spray drying are separated from the dryinggas and evaporated solvent, allowing the particles to be collected. Afilter may also be used to separate and collect the particles producedby spray drying.

As used herein, the term chemical shift difference refers to thedifference in chemical shift resonance between a reference chemicalshift resonance and another chemical shift resonance in the same NMRspectrum. In the present patent application, the chemical shiftdifferences were calculated by subtracting the lowest ppm resonance(reference chemical shift resonance) in the NMR spectrum of chemicalshifts in the area of 100 to 180 ppm from another (observed) ppmresonance in the same NMR spectrum of chemical shifts in the area of 100to 180 ppm. These chemical shift differences provide a measurement for asubstance, for example carvedilol phosphate, of the present inventionthat compensates for a phenomenon in NMR spectroscopy wherein, dependingon the instrumentation and calibration method used, a shift in theSS-NMR “footprint” is observed. This shift in the SS-NMR “footprint”,having chemical shift resonances at a certain positions, is such thatalthough the individual chemical shift resonances have altered, thedistance between each chemical shift resonance and the next is retained.

Carvedilol Phosphate

In one embodiment, the invention provides an amorphous form ofcarvedilol phosphate. The amorphous form of carvedilol phosphate may befree of any crystalline form.

In another embodiment, the invention encompasses a process for preparingthe amorphous form of carvedilol phosphate. The amorphous form ofcarvedilol phosphate can be prepared by precipitation from ethanol.Preferably, the carvedilol phosphate is prepared by precipitation from amixture of ethanol and water.

Accordingly, the invention provides a method for preparing amorphouscarvedilol phosphate comprising:

-   -   (a) precipitating amorphous carvedilol phosphate from a solution        of carvedilol and phosphoric acid in a mixture of ethanol and        water; and    -   (b) recovering the amorphous carvedilol phosphate.

In one preferred embodiment, the process comprises: (a) providing asolution of carvedilol, phosphoric acid, and ethanol; (b) optionallyadding water to the solution to accelerate precipitation of thecarvedilol phosphate; and (c) recovering the carvedilol phosphate inamorphous form.

The carvedilol and phosphoric acid in step (a) can be present in a molarratio of about 5:1 to about 1:1, preferably about 4:1 to about 2:1, morepreferably about 2.5:1 to about 3.5:1, and even more preferably about3:1. The solution of step (a) may be prepared by combining carvediloland ethanol to form a mixture and then slowly adding phosphoric acid tothe mixture. The solution of step (a) may also be prepared by combiningphosphoric acid and ethanol and then adding carvedilol or by addingcarvedilol and phosphoric acid more or less simultaneously to ethanol.

The ingredients in step (a) may be heated in order to achievedissolution. Stirring may also be employed to promote dissolution. Inone embodiment, heating is carried out to about 60° C. to about refluxtemperature, followed by cooling to a temperature of about 0° C. toabout 30° C. Preferably, the ingredients in step (a) are heated toreflux (about 78° C. to 82° C.) and maintained at reflux for a period oftime. More preferably, the ingredients in step (a) are maintained atreflux for about 5 to about 10 minutes, or for about 5 to about 100minutes, optionally, with stirring.

If the solution of step (a) is heated, the solution is preferably cooledto about 20° C. to about 35° C., preferably to about room temperature(about 20-23° C.), before adding the water of step (b). Preferably,after water is added to the solution of step (a), the resulting mixtureis stirred at about 20° C. to about 35° C., preferably at about roomtemperature (about 20-23° C.). More preferably, the mixture is stirredat about 20° C. to about 35° C. for about 4 to about 16 hours, or about6 to about 12 hours, or about 8 to about 10 hours, or overnight.

In certain embodiments, the ratio of water to ethanol is about 3:1 toabout 1:3, preferably about 2:1 to about 1:2, and more preferably about1:1 (v/v).

In certain embodiments, the ratio of carvedilol to ethanol is about 1:5to about 1:30, preferably about 1:10 to about 1:20, and more preferablyabout 1:15 (g/ml).

In certain embodiments, the ratio of carvedilol to water is about 1:5 toabout 1:30, preferably about 1:10 to about 1:20, and more preferablyabout 1:15 (g/ml).

The precipitated carvedilol phosphate may be recovered by any methodknown to the skilled artisan. Preferably, the carvedilol phosphate isrecovered from the mixture by filtration, and then dried under reducedpressure (<1 atmosphere). Preferably, the drying can be at elevatedtemperature, e.g., in an oven at about 40° C. to about 60° C.,preferably about 50° C.

Amorphous solids, in contrast to crystalline forms, do not possess adistinguishable crystal lattice and do not have an orderly arrangementof structural units. Amorphous forms are generally more soluble, andthus they are desirable for pharmaceutical purposes because thebioavailability of amorphous compounds may be greater than theircrystalline counterparts.

Amorphous carvedilol phosphate may be analyzed to determine theamorphous nature of the product. The powder X-ray diffraction (“PXRD”)pattern of amorphous carvedilol phosphate would show no peakscharacteristic of crystalline forms of carvedilol phosphate, thusdemonstrating the amorphous nature of the product. The presence of peakscharacteristic of crystalline forms would indicate presence ofcrystalline carvedilol phosphate. A representative PXRD pattern foramorphous carvedilol phosphate is depicted in FIG. 1.

Preferably, the amorphous carvedilol phosphate comprises less than about20% crystalline carvedilol and or carvedilol phosphate salts by weight,more preferably less than about 10% by weight, and even more preferablyless than about 5% by weight, more preferably less than 1% by weight.The presence of a particular crystalline carvedilol can be determined bythe presence of PXRD peaks characteristic of crystalline forms ofcarvedilol phosphate salts. The amount of crystallinity is quantified bymethods known in the art like “crystallinity index” available to mostXRD softwares.

In certain embodiments, the amorphous carvedilol phosphate comprisesless than about 20% of Form I crystalline carvedilol by weight, morepreferably less than about 10% by weight, and even more preferably lessthan about 5% by weight of Form I, as judged by the presence of PXRDpeaks characteristic of Form I crystalline carvedilol. Form I isdisclosed in European Patent Application EP 0893440.

Carvedilol Hydrogen Phosphate

The invention provides crystalline forms and an amorphous form ofcarvedilol hydrogen phosphate, which are more readily soluble thancarvedilol free base. The amorphous carvedilol hydrogensulfate of thepresent invention has an XRD spectrum as substantially depicted in FIGS.9 and 10.

Also provided is a process for preparing amorphous carvedilol hydrogenphosphate comprising dissolving carvedilol hydrogen phosphate in C₁-C₈alcohols or in a mixture of C3-7 ketones with water, followed by solventremoval. Preferably the carvedilol hydrogen phosphate is dissolved inacetone and the ratio of acetone/water is about 2:1 (v/v).

Preferably the solvent is removed by fast evaporation, more preferablyby spray drying. Spray drying can be carried out with an inlettemperature of about 80° C. to about 120° C. and an outlet temperatureof below about 100° C. In one embodiment the spray drying is carried outwith an inlet temperature of about 95° C. to about 105° C. and an outlettemperature of below about 40° C.

In one embodiment, the invention encompasses a crystalline form ofcarvedilol hydrogen phosphate, referred to herein as Form G,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 6.5, 9.7, 13.0, 16.0 and 17.8degrees two theta ±0.2 degrees two theta; a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about 145.8, 141.7 and 110.8±0.2ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 43.8, 39.7 and 8.8±0.1 ppm. The lowest ppm resonance in thechemical shift area of 100 to 180 ppm is typically at about 102.0±1 ppm.The X-ray powder diffractogram of Form G is substantially shown in FIG.2. The solid-state ¹³C NMR spectrum of Form G is substantially shown inFIGS. 3 and/or 3 a.

Form G can also be characterized by any five peaks selected from thefollowing list of PXRD peaks at about: 6.5, 9.7, 13.0, 13.5, 16.0, 17.8,22.8 and 23.2±0.2 degrees two theta. In another embodiment Form G ischaracterized by data selected from: X-ray powder diffractionreflections at about: 6.5, 9.7, 16.0, 18.4 and 23.2 degrees two theta±0.2 degrees two theta.

Form G, and can be further characterized by data selected from the groupconsisting of: X-ray powder diffraction reflections at about 18.5, 19.5,20.9, 23.1 and 24.7 degrees two-theta, ±0.2 degrees two-theta; asolid-state ¹³C-NMR spectrum having chemical shift resonances at about154.5, 146.5 and 138.8±0.2 ppm; and a solid-state ¹³C NMR spectrumhaving chemical shift differences between the lowest ppm resonance inthe chemical shift area of 100 to 180 ppm and another in the chemicalshift area of 100 to 180 ppm of 52.5, 44.5 and 36.8±0.1 ppm. The lowestppm resonance in the chemical shift area of 100 to 180 ppm is typicallyat about 102.0±1 ppm.

Form G has a weight loss, as measured by TGA, of between about 4.5-11.0%by weight.

In another embodiment, the invention encompasses a process for preparingcarvedilol hydrogen phosphate Form G comprising: (a) combiningcarvedilol, phosphoric acid, and methanol to obtain a solution; (b)combining the solution with water to obtain a solid; and (c) recoveringcarvedilol hydrogen phosphate Form G.

The carvedilol and phosphoric acid in step (a) are preferably combinedin a molar ratio of about 2:1. The solution of step (a) may be preparedby combining carvedilol and methanol to form a mixture and then slowlyadding phosphoric acid to the mixture. Alternatively, the carvedilol andphosphoric acid may be added more or less simultaneously to themethanol.

The ratio of carvedilol to water can be about 1:8 (g/ml) to about 1:12(g/ml). Preferably, the ratio of carvedilol to water is about 1:10(g/ml).

The ingredients in step (a) may be heated to in order to achievedissolution. Stirring may also be employed to promote dissolution.Preferably, the ingredients in step (a) are heated to reflux.

If the solution of step (a) is heated, the solution is preferably cooledto about 20° C. to about 35° C. before combining the solution with waterin step (b).

The precipitated carvedilol hydrogen phosphate Form G may be recoveredby any method known to the skilled artisan. Preferably, the carvedilolhydrogen phosphate Form G is recovered from the mixture by filtration,and then dried under reduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a process for preparingcarvedilol hydrogen phosphate Form G comprising: (a) combiningcarvedilol, phosphoric acid, and acetone/water to obtain a mixture; (b)maintaining the mixture to obtain a solid; and (c) recovering carvedilolhydrogen phosphate Form G.

The carvedilol and phosphoric acid in step (a) are preferably combinedin a molar ratio of about 2:1. In some embodiments, the molar ratio ofphosphoric acid to carvedilol is about 0.8:1 to about 2.5:1. The mixtureof step (a) may be prepared by first combining carvedilol andacetone/water and then slowly adding phosphoric acid to the mixture.Alternatively, the and phosphoric acid may be added more or lesssimultaneously to the acetone/water mixture.

Preferably, the acetone/water in step (a) is in a ratio of from about4:1 to about 2:1 (v/v), and most preferably at about 3:1 (v/v).

Preferably, in step (b), the mixture is maintained, while stirring, at atemperature of about 20° C. to about 35° C., preferably at about roomtemperature (about 20° C. to about 23° C.) for about 12 hours.

The precipitated carvedilol hydrogen phosphate Form G may be recoveredby any method known to the skilled artisan. Preferably, the carvedilolhydrogen phosphate Form G is recovered from the mixture by filtration,and then dried under reduced pressure (<1 atmosphere).

Form G can also be prepared by slurrying Form R, F1 or I in water. Theslurry may be carried out for about 6 hours to about 3 days. The productis recovered and may be dried, such as at about 40° C. to about 60° C.

In another embodiment, the invention encompasses a process for preparinga phosphate salt of carvedilol, characterized by data selected from thegroup consisting of: X-ray powder diffraction reflections at about: 6.5,9.7, 13.0, 16.0 and 17.8 degrees two theta ±0.2 degrees two theta; asolid-state ¹³C-NMR spectrum having chemical shift resonances at about145.8, 141.7 and 110.8±0.2 ppm; and a solid-state ¹³C NMR spectrumhaving chemical shift differences between the lowest ppm resonance inthe chemical shift area of 100 to 180 ppm and another in the chemicalshift area of 100 to 180 ppm of about 43.8, 39.7 and 8.8±0.1 ppm. Thelowest ppm resonance in the chemical shift area of 100 to 180 ppm istypically at about 102.0±1 ppm. The X-ray powder diffractogram of Form Gis substantially shown in FIG. 2. The solid-state ¹³C NMR spectrum ofForm G is substantially shown in FIGS. 3 and/or 3 a.

Form G can also be characterized by any five peaks selected from thefollowing list of PXRD peaks at about: 6.5, 9.7, 13.0, 13.5, 16.0, 17.8,22.8 and 23.2±0.2 degrees two theta. In one embodiment, Form G ischaracterized by data selected from: X-ray powder diffractionreflections at about: 6.5, 9.7, 13.5, 16.0 and 17.8 degrees two theta±0.2 degrees two theta. In another embodiment Form G is characterized bydata selected from: X-ray powder diffraction reflections at about: 6.5,9.7, 16.0, 18.4 and 23.2 degrees two theta ±0.2 degrees two theta.

In another embodiment the present invention provides a method forpreparing Form G comprising: (a) providing a suspension of amorphouscarvedilol dihydrogen phosphate in phosphoric acid and water at a pH ofabout 3.5-7; (b) maintaining the mixture for at least 15 hours; and (c)recovering the phosphate salt of carvedilol.

Typically, in step (a) an aqueous solution of phosphoric acid iscombined with the amorphous carvedilol dihydrogen phosphate.

Preferably, in step (b), the suspension is maintained, while stirring,at a temperature of about 20° C. to about 35° C., preferably at about25° C., for about 19-21 hours.

The precipitated Form G may be recovered by any method known to theskilled artisan. Preferably, the carvedilol hydrogen phosphate Form G isrecovered from the mixture by filtration, and then dried under reducedpressure (<1 atmosphere).

In another embodiment, the invention encompasses a process for preparingcarvedilol hydrogen phosphate Form G comprising slurrying carvediloldihydrogen phosphate Form R in water.

The ingredients are preferably maintained, while stirring, at atemperature of about 20° C. to about 35° C., preferably about roomtemperature (about 20° C. to about 23° C.), for about 12 hours to about24 hours.

The obtained carvedilol hydrogen phosphate may be further recovered byany method known to the skilled artisan. Preferably, the carvediloldihydrogen phosphate is recovered by filtration, and then dried underreduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a process for preparingcarvedilol hydrogen phosphate Form G comprising slurrying carvediloldihydrogen phosphate Form F1 in water.

The ingredients are preferably maintained, while stirring, at atemperature of about 20° C. to about 35° C., preferably about roomtemperature (about 20° C. to about 23° C.), for about 12 hours to about24 hours.

The obtained carvedilol hydrogen phosphate may be further recovered byany method known to the skilled artisan. Preferably, the carvediloldihydrogen phosphate is recovered by filtration, and then dried underreduced pressure (<1 atmosphere).

In one embodiment, the invention encompasses a crystalline form ofcarvedilol hydrogen phosphate, referred to herein as Form H,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 6.4, 6.6, 9.4, 14.5 and 15.4degrees two theta ±0.2 degrees two theta; X-ray powder diffractionreflections at about: 6.6, 9.7, 13.0, 13.8 and 15.6 degrees two theta±0.2 degrees two theta; any five peaks selected from the following listof PXRD peaks at about: 6.5, 6.8, 9.6, 13.0, 13.6, 15.6, 17.5 and28.7±0.2 degrees two theta; X-ray powder diffraction reflections atabout: 6.5, 9.6, 13.0, 13.6 and 18.7 degrees two theta ±0.2 degrees twotheta; X-ray powder diffraction reflections at about: 6.5, 9.6, 13.6,18.7 and 20.2 degrees two theta ±0.2 degrees two theta; a solid-state¹³C-NMR spectrum having chemical shift resonances at about 146.3, 142.6and 139.1±0.2 ppm; and a solid-state ¹³C NMR spectrum having chemicalshift differences between the lowest ppm resonance in the chemical shiftarea of 100 to 180 ppm and another in the chemical shift area of 100 to180 ppm of about 34, 30.3 and 26.8±0.1 ppm. The lowest ppm resonance inthe chemical shift area of 100 to 180 ppm is typically at about 112.3±1ppm.

The X-ray powder diffractogram of Form H is substantially shown in FIG.4 or 5. The solid-state ¹³C NMR spectrum of Form H is substantiallyshown in FIGS. 6 and/or 6 a.

Form H, and can be further characterized by data selected from the groupconsisting of: X-ray powder diffraction reflections at about 18.4, 19.3,20.4, 22.4 and 25.3 degrees two-theta, ±0.2 degrees two-theta; X-raypowder diffraction reflections at about 18.6, 19.5, 20.6, 22.6 and 25.0degrees two-theta, ±0.2 degrees two-theta; a solid-state ¹³C-NMRspectrum having chemical shift resonances at about 155.3, 122.2 and112.3±0.2 ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of 43, 9.9 and 0±0.1 ppm. The lowest ppm resonance in the chemicalshift area of 100 to 180 ppm is typically at about 112.3±1 ppm.

Form H has a weight loss, as measured by TGA, of between about 2.9-7.1%by weight.

In another embodiment, the invention encompasses a process for preparingcarvedilol hydrogen phosphate Form H comprising: (a) combiningcarvedilol, phosphoric acid, and ethanol/water to obtain a mixture; (b)maintaining the mixture for at least 6 hours to obtain a solid; and (c)recovering carvedilol hydrogen phosphate Form H.

The carvedilol and phosphoric acid in step (a) are preferably combinedin a molar ratio of about 2.5:1 to about 0.8:1, more preferably about2:1. The mixture of step (a) may be prepared by first combiningcarvedilol and ethanol, then slowly adding phosphoric acid to themixture, heating to reflux and finally adding water.

Preferably, the ethanol/water in step (a) is in a ratio of from about1:1 to about 7:1, most preferably about 5:1.

If the solution of step (a) is heated, the solution is cooled to about20° C. to about 35° C., preferably to about room temperature (about 20°C. to about 23° C.), prior to step (b).

Preferably, in step (b), the mixture is maintained, while stirring, at atemperature of about 20° C. to about 35° C., preferably about roomtemperature (about 20° C. to about 23° C.), for about 12 hours.

The precipitated carvedilol hydrogen phosphate Form H may be recoveredby any method known to the skilled artisan. Preferably, the carvedilolhydrogen phosphate Form H is recovered from the mixture by filtration,and then dried under reduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a crystalline form ofcarvedilol hydrogen phosphate, referred to herein as Form K,characterized by X-ray powder diffraction reflections at about: 6.3,9.8, 12.7, 13.2 and 16.9 degrees two theta ±0.2 degrees two theta;

Form K has an X-ray powder diffractogram as substantially shown in FIG.7.

Form K can also be characterized by any five peaks selected from thefollowing list of PXRD peaks at about: 6.3, 9.8, 12.7, 13.2, 16.3, 16.9,18.3 and 19.0±0.2 degrees two theta.

Form K can also be characterized by data selected from: X-ray powderdiffraction reflections at about: 6.3, 9.8, 16.9, 18.3 and 23.2 degreestwo theta ±0.2 degrees two theta.

Form K can also be characterized by data selected from: X-ray powderdiffraction reflections at about: 6.3, 9.8, 14.9, 20.1 and 28.2 degreestwo theta ±0.2 degrees two theta.

Form K can be further characterized by X-ray powder diffractionreflections at about 16.3, 20.1, 20.7, 24.1 and 24.8 degrees two-theta,±0.2 degrees two-theta

Form K has a weight loss, as measured by TGA, of between about 9.1-13.0%by weight.

In another embodiment, the invention encompasses a process for preparingcarvedilol hydrogen phosphate Form K comprising exposing carvedilolhydrogen phosphate Form H to more than about 80% relative humidity forat least about 7 days.

Fork K can also be prepared by combining carvedilol in acetone/water,preferably (3:1) solution higher than 50 ml and adding phosphoric acid,preferably about 85% concentration. The resulting reaction mixture canthen be stirred and maintained to obtain a precipitate. The product canbe recovered and dried, under a pressure of less than one atmosphere.

In another embodiment, the invention encompasses a process for preparingan amorphous form of carvedilol hydrogen phosphate. This processcomprises dissolving carvedilol hydrogen phosphate in C₁-C₈ alcohols orin a mixture of C₃₋₇ ketones with water, followed by solvent removal.

Preferably, the solvent in which carvedilol hydrogen phosphate isdissolved is methanol or acetone.

Whenever acetone is used, the ratio of acetone/water is preferably fromabout 3:1 to about 1:1 (v/v), and more preferably about 2:1 (v/v).

Preferably, removing the solvent is performed using spray drying.

The processes of the present invention may preferably employ spraydrying with an inlet temperature of about 80° C. to about 120° C., andan outlet temperature of less than about 100° C.

The processes of the present invention may preferably employ spraydrying with an inlet temperature of about 95° C. to about 105° C.,preferably about 100° C.

The spray drying may preferably be conducted with an outlet temperatureof below the inlet temperature, preferably below about 35° C. to about45° C., and more preferably below about 40° C.

The drying gas used in the process of the present invention may be anysuitable gas, although inert gases such as nitrogen, nitrogen-enrichedair, and argon are preferred.

The carvedilol dihydrogen phosphate product produced by spray drying maybe recovered by techniques commonly used in the art, such as using acyclone or a filter.

The carvedilol hydrogen phosphate starting material used for theprocesses of the present invention may be any crystalline form ofcarvedilol hydrogen phosphate, including any solvates and hydrates. Withprocesses where carvedilol hydrogen phosphate goes into solution, theform of the starting material is of minimal relevance since any solidstate structure is lost in solution.

In another embodiment, the invention encompasses a phosphate salt ofcarvedilol, referred to herein as Form Q, characterized by X-ray powderdiffraction reflections at about: 6.2, 7.3, 14.5, 17.5 and 21.3 degreestwo theta ±0.2 degrees two theta.

In another embodiment, Form Q having X-ray powder diffractogram assubstantially shown in FIG. 8.

Form Q has a weight loss, as measured by TGA, of about 3.8% by weight.

Form Q Carvedilol hydrogen phosphate can be prepared by exposing Form Kto a relative humidity of less than about 20%, preferably about 0%relative humidity (RH). Exposure is preferably from about 1 day to about10 days, more preferably about 7 days. The process can be carried out atroom temperature (about 20-23° C.).

Each of Forms G, H, K and Q contain less than comprises less than about20% crystalline carvedilol phosphate salts by weight, more preferablyless than about 10% by weight, and even more preferably less than about5% by weight add: less than 1%. The presence of a particular crystallinecarvedilol can be determined by the presence of PXRD peakscharacteristic of crystalline carvedilol phosphate salts.

In certain embodiments, Each of Forms G, H, K and Q contain less than50%, less than 25%, less than 10%, less than 5%, or less than 1% byweight of carvedilol dihydrogen phosphate Form I. In certainembodiments, Each of Form G, H, K and Q is provided as a solid materialin which Each of Form G, H, K and Q represents 50%, 75%, 90%, 95%, or99% by weight of the solid material.

In another embodiment, the invention encompasses an amorphous form ofcarvedilol hydrogen phosphate. A typical powder x-ray diffractiondiagram for the amorphous form is shown in FIGS. 9 and 10.

Amorphous carvedilol hydrogen phosphate may be analyzed to determine theamorphous nature of the product. The powder X-ray diffraction (“PXRD”)pattern of amorphous carvedilol hydrogen phosphate would show no peakscharacteristic of crystalline forms of carvedilol hydrogen phosphate,thus demonstrating the amorphous nature of the product. The presence ofpeaks characteristic of crystalline forms would indicate presence ofcrystalline carvedilol hydrogen phosphate.

Preferably, the amorphous carvedilol hydrogen phosphate comprises lessthan about 20% crystalline carvedilol and or carvedilol phosphate saltsby weight, more preferably less than about 10% by weight, and even morepreferably less than about 5% by weight, and even more preferably lessthan about 1% by weight. The presence of crystalline carvedilol hydrogenphosphate can be determined by the presence of PXRD peaks characteristicof crystalline carvedilol phosphate salts.

In certain embodiments, the amorphous carvedilol hydrogen phosphatecomprises less than about 20% of Form I crystalline carvedilol byweight, more preferably less than about 10% by weight, and even morepreferably less than about 5% by weight of Form I, as judged by thepresence of PXRD peaks characteristic of Form I crystalline carvedilol.Form I is disclosed in European Patent Application EP 0893440.

Carvedilol Dihydrogen Phosphate

The invention provides crystalline forms of carvedilol dihydrogenphosphate as well as processes for obtaining crystalline forms ofcarvedilol dihydrogen phosphate, which are more readily soluble thancarvedilol free base.

In one embodiment the present invention provides processes for preparingcarvedilol dihydrogen phosphate Form I. Form I is characterized by dataselected from the group consisting of: X-ray powder diffractionreflections at about: 7.0, 8.0, 9.2, 11.4 and 16.0 degrees two theta±0.2 degrees two theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 154.5, 146.5, 139.7 and 122.1±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 50.7,42.7 and 18.3±0.1 ppm. X-ray diffractogram substantially shown in FIG.11; solid-state ¹³C-NMR substantially shown in FIG. 12.

I can be prepared by exposing Form F to about 100% humidity at elevatedtemperature, preferably about 30° C. to about 80° C., more preferablyabout 60° C. Preferably the exposure is carried out for about 1 to about10 days, more preferably for about 7 days.

In one embodiment, the invention encompasses a process for preparingcrystalline carvedilol dihydrogen phosphate Form I, comprising:combining carvedilol, phosphoric acid and a solvent selected from thegroup consisting of C₄-C₈ alcohols, C₅-C₁₀ aliphatic hydrocarbons, C₆₋₁₂aromatic hydrocarbons, C₃-C₇ ketones C₄-C₈ ethers, C₃-C₇ esters andacetonitrile and precipitating carvedilol dihydrogen phosphate Form Ifrom the reaction mixture.

Preferably, the solvent is selected from the group consisting of:butanol, 2-butanol, n-butanol, tert-butanol, heptane, acetone, methylisobutyl ketone (MIBK), methyl ethyl ketone (MEK), propylene glycolmonomethyl ether (PGME), THF, methyl tert-butyl ether (MTBE), methylacetate, isobutyl acetate, ethyl acetate and acetonitrile. Morepreferably, the solvent is selected from the group consisting of:methanol, ethanol, isopropyl alcohol (IPA), and THF. Acetone is not usedin a mixture with another solvent.

C₁-C₄ alcohols can be used, but the process with methanol and ethanol iscarried out at about room temperature (about 20-23° C.). Recovery frommethanol and ethanol is carried out rapidly, preferably less than about4 hours. The process with isopropyl alcohol is carried out at atemperature higher than about 55° C.

The carvedilol and phosphoric acid are preferably present in a molarratio of about 1:1. Precipitation may be obtained from a solution or aslurry of carvedilol, phosphoric acid and the solvent.

The ingredients may be heated in order to achieve dissolution. Stirringmay also be employed to promote dissolution. Preferably, the ingredientsare heated to reflux. Whether the ingredients are heated, the processmay further comprise cooling, to induce crystallization.

Whenever precipitation occurs from a slurry of carvedilol, phosphoricacid and the solvent, the ingredients are preferably maintained, whilestirring, at a temperature of about 20° C. to about 35° C. for about 12hours to about 24 hours. When precipitation occurs from a slurry inethanol, stirring is employed for about 1 hour.

Precipitation may occur with or without the presence of water, exceptwhen acetone is used water is absent and when methanol is used water ispresent. The precipitated carvedilol dihydrogen phosphate Form I may berecovered by any method known to the skilled artisan. Preferably, thecarvedilol dihydrogen phosphate Form I is recovered by filtration, andthen dried under reduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a process for preparingcrystalline carvedilol dihydrogen phosphate Form I, is characterized bydata selected from the group consisting of: X-ray powder diffractionreflections at about: 7.0, 8.0, 9.2, 11.4 and 16.0 degrees two theta±0.2 degrees two theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 154.5, 146.5, 139.7 and 122.1±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 50.7,42.7 and 18.3±0.1 ppm. X-ray diffractogram substantially shown in FIG.11; solid-state ¹³C-NMR substantially shown in FIG. 12 comprisingslurrying carvedilol dihydrogen phosphate Form R in ethanol.

The carvedilol dihydrogen phosphate Form R starting material may beobtained as described below.

The ingredients are preferably maintained, while stirring, at atemperature of about 20° C. to about 35° C. for about 12 hours to about24 hours.

Preferably, absolute ethanol is used. “Absolute” or “technical grade” or“anhydrous” are common terms used in the art to refer to alcohols havingless than about 2% water by volume.

The obtained carvedilol dihydrogen phosphate Form I may be furtherrecovered by any method known to the skilled artisan. Preferably, thecarvedilol dihydrogen phosphate Form I is recovered by filtration, andthen dried under reduced pressure (<1 atmosphere).

From I can be prepared by heating Form, N, P carvedilol dihydrogenphosphate, preferably to about 60° C. to about 140° C., more preferablyabout 80° C.-120° C. Preferably the heating is carried out for about 10minutes to about 3 hours, more preferably about 30 minutes.

From I can be prepared by heating Form L1, R and amorphous carvediloldihydrogen phosphate, preferably to about 110° C. to about 150° C., morepreferably about 120° C.-140° C. Preferably the heating is carried outfor about 10 minutes to about 3 hours, more preferably about 30 minutes.

Form I can also be prepared by slurrying Form F1, amorphous carvediloldihydrogen phosphate, Form R, or Form N in acetone. The slurry can bemaintained until obtaining the transformation. The slurry may bemaintained for about 12 hours to about 5 days, preferably for about 1day. The crystals can then be recovered by conventional techniques, andcan also be dried such as at a temperature of about 50° C. to about 90°C., and a pressure of below one atmosphere.

Form I can also be prepared by putting Form P or Form N under pressure,such as pressure of about 1 ton to about 3 ton, preferably about 2 ton.

Form I can also be prepared by grinding Forms F and P, such as for about1 to about 3 minutes.

Form I can also be prepared by placing amorphous carvedilol dihydrogenphosphate in an atmosphere of n-propanol, iso-propanol, butanol, acetoneand ethyl acetate.

Form I can be prepared by slurrying Form N in water. The slurry can becarried out for about 12 hours to about 5 days, preferably about 12hours. The product can then be recovered by conventional techniques,such as filtration, and then dried, such as at about 40° C. to about 60°C., under pressure below one atmosphere.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form F,characterized by data selected from: X-ray powder diffractionreflections at about: 7.7, 8.7, 16.8 and 22.8 degrees two theta ±0.2degrees two theta; X-ray powder diffraction reflections at about: 7.6,8.6, 16.7 and 22.8 degrees two theta ±0.2 degrees two theta; X-raypowder diffraction reflections at about: 7.7, 8.7, 16.8, 22.8 and 26.5degrees two theta ±0.2 degrees two theta; and X-ray powder diffractionreflections at about: 7.6, 8.6, 16.7, 22.8 and 26.5 degrees two theta±0.2 degrees two theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 149.8, 145.4 and 140.7±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 50.6,46.2 and 41.5±0.1 ppm. The lowest ppm resonance in the chemical shiftarea of 100 to 180 ppm is typically at about 99.2±1 ppm; a solid-state¹³C-NMR spectrum having chemical shift resonances at about 149.8, 145.4,138.5 and 140.7±0.2 ppm; and a solid-state ¹³C NMR spectrum havingchemical shift differences between the lowest ppm resonance in thechemical shift area of 100 to 180 ppm and another in the chemical shiftarea of 100 to 180 ppm of about 50.6, 46.2, 39.3 and 41.5±0.1 ppm. Thelowest ppm resonance in the chemical shift area of 100 to 180 ppm istypically at about 99.2±1 ppm.

Form F has an X-ray powder diffractogram as substantially shown in FIG.23 or 24. Form F has a solid-state ¹³C NMR spectrum as substantiallyshown in FIG. 25 and or 25 a.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form F,characterized by data selected from: X-ray powder diffractionreflections at about: 7.7, 8.7, 13.5, 15.2 and 22.9 degrees two theta±0.2 degrees two theta; X-ray powder diffraction reflections at about:7.6, 8.6, 13.4, 15.1 and 22.8 degrees two theta ±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form F,characterized by data selected from: X-ray powder diffractionreflections at about: 7.7, 13.5, 15.2, 18.3 and 18.9 degrees two theta±0.2 degrees two theta; X-ray powder diffraction reflections at about:7.6, 13.4, 15.1, 18.2 and 18.8 degrees two theta ±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form F,characterized by data selected from: X-ray powder diffractionreflections at about: 7.7, 13.5, 15.2, 17.2 and 21.5 degrees two theta±0.2 degrees two theta; X-ray powder diffraction reflections at about:7.6, 13.4, 15.1, 17.1 and 21.4 degrees two theta ±0.2 degrees two theta.

Form F can be further characterized by data selected from: X-ray powderdiffraction reflections at about 10.0, 11.6, 13.6, 15.2 and 27.1 degreestwo-theta, ±0.2 degrees two-theta; and X-ray powder diffractionreflections at about 9.9, 11.5, 13.4, 15.1 and 27.0 degrees two-theta,±0.2 degrees two-theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 146.7, 138.5 and 111.8±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 47.5,39.3 and 12.6±0.1 ppm. The lowest ppm resonance in the chemical shiftarea of 100 to 180 ppm is typically at about 99.2±1 ppm. Typical powderx-ray diffractograms for Form F are shown in FIGS. 23 and 24. A typicalsolid-state ¹³C-NMR spectrum of Form F is shown in FIGS. 25 and/or 25 a.

Form F has a weight loss, as measured by TGA, of about 2.9% by weight,while it has water content, as measured by KF, of about 0.2% by weight.This corresponds to carvedilol dihydrogen phosphate hemimethanolate. GCmeasurement of residual solvents gives about 30,800-32,300 ppm ofmethanol confirming presence of hemimethanolate solvate of carvediloldihydrogen phosphate.

In another embodiment, the invention encompasses a process forcrystallizing carvedilol dihydrogen phosphate Form F from a solution ofcarvedilol, phosphoric acid and methanol.

The carvedilol and phosphoric acid are preferably present in a molarratio of about 0.8:1 to about 1.2:1, more preferably about 1:1.

The ingredients may be heated in order to achieve dissolution. Stirringmay also be employed to promote dissolution. Preferably, the ingredientsare heated to reflux. Whether the ingredients are heated, the processmay further comprise cooling, to induce crystallization.

Crystallization occurs without addition of water; a minimal amount ofwater may be present from the phosphoric acid. Preferably, the methanolis anhydrous, i.e., contains less than 2% water by volume.

Crystallization may be carried out for about 5 minutes to about 30minutes or for about 5 minutes to about 300 minutes.

The carvedilol dihydrogen phosphate may be recovered by any method knownto the skilled artisan. Preferably, the carvedilol dihydrogen phosphateis recovered from the mixture by filtration, and then dried underreduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a process forcrystallizing carvedilol dihydrogen phosphate Form F from a solution ofcarvedilol dihydrogen phosphate and methanol.

The starting material used for the processes for obtaining carvediloldihydrogen phosphate Form F may be any crystalline or amorphous form ofcarvedilol dihydrogen phosphate, including various solvates andhydrates. With crystallization processes, the crystalline form of thestarting material does not usually affect the final result.

Preferably, the carvedilol dihydrogen phosphate starting material iscarvedilol dihydrogen phosphate Form I.

The ingredients may be heated in order to achieve dissolution. Stirringmay also be employed to promote dissolution. Preferably, the ingredientsare heated to reflux. Whether the ingredients are heated, the processmay further comprise cooling, to induce crystallization.

Crystallization occurs without addition of water; a minimal amount ofwater may be present from the phosphoric acid.

The carvedilol dihydrogen phosphate may be recovered by any method knownto the skilled artisan. Preferably, the carvedilol dihydrogen phosphateis recovered from the mixture by filtration, and then dried underreduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form F1,characterized by data selected from: X-ray powder diffractionreflections at about: 7.6, 9.8, 10.9, 21.2 and 25.0 degrees two theta±0.2 degrees two theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 155.3, 145.3 and 127.7±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 52.6,42.6 and 25±0.1 ppm. The lowest ppm resonance in the chemical shift areaof 100 to 180 ppm is typically at about 102.7±1 ppm.

In another embodiment, Form F1 having X-ray powder diffractogram assubstantially shown in FIGS. 26 and 27.

In another embodiment, Form F1 having solid-state ¹³C NMR spectrum assubstantially shown in FIGS. 28 and 28 a.

Form F1 can also be characterized by X-ray powder diffractionreflections at about: 7.6, 10.9, 13.3, 15.2 and 18.8 degrees two theta±0.2 degrees two theta.

Form F1 can also be characterized by X-ray powder diffractionreflections at about: 7.6, 8.5, 9.8, 15.2 and 16.9±0.2 degrees twotheta.

Form F1 can also be characterized by X-ray powder diffractionreflections at about: 7.6, 9.8, 10.9, 14.7, 15.2 and 22.8±0.2 degreestwo theta.

Form F1 can also be characterized by X-ray powder diffractionreflections at about: 7.6, 8.5, 9.8, 13.3 and 15.2±0.2 degrees twotheta.

Form F1 can be further characterized by X-ray powder diffractionreflections at about 15.7 and 28.0 degrees two-theta, ±0.2 degreestwo-theta. A typical powder x-ray diffractogram for Form F1 is shown inFIGS. 26 and 27.

Form F1 can be distinguished from Form F by having four diffractionpeaks in the area of about 19-20.7 degrees two-theta, whereas Form F hasonly three; further, Form F1 has four diffraction peaks in the area ofabout 24.8-26.0 degrees two-theta, whereas Form F has two; lastly, FormF1 has three diffracted peaks in the area of about 27.8-29.3 degreestwo-theta, whereas Form F has two.

Form F1 has a weight loss, as measured by GC measurement of residualsolvents between about 42,500-47,000 ppm of ethanol. Hence, Form F1 ishemiethanolate solvate of carvedilol dihydrogen phosphate.

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form F1 comprising precipitation from aslurry of carvedilol, phosphoric acid and ethanol, wherein the slurry isstirred for at least about 4 hours.

The carvedilol and phosphoric acid are preferably present in a molarratio of about 0.8:1 to about 1.2:1, and more preferably about 1:1.

Preferably, absolute ethanol is used.

Preferably, the ingredients are heated to reflux. Whether theingredients are heated, the process may further comprise cooling, toinduce precipitation.

The carvedilol dihydrogen phosphate may be recovered by any method knownto the skilled artisan. Preferably, the carvedilol dihydrogen phosphateis recovered from the mixture by filtration, and then dried underreduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form F1 comprising precipitation from aslurry of carvedilol dihydrogen phosphate and ethanol, wherein theslurry is maintained for at least about 4 hours.

Preferably, the carvedilol dihydrogen phosphate starting material iscarvedilol dihydrogen phosphate Form I, Form N or Form R.

Preferably, absolute ethanol is used.

Preferably, the ingredients are heated to reflux. Whether theingredients are heated, the process may further comprise cooling, toinduce precipitation.

The carvedilol dihydrogen phosphate may be recovered by any method knownto the skilled artisan. Preferably, the carvedilol dihydrogen phosphateis recovered from the mixture by filtration, and then dried underreduced pressure (<1 atmosphere).

In one embodiment, carvedilol base is combined with ethanol and heatedto obtain a solution. Heating is preferably carried out of about 65° C.to about 82° C. (reflux temperature), preferably about 78-82° C.Phosphoric acid and optionally an additional amount of ethanol are addedto the solution. The solution is cooled, preferably to about 10° C. toabout 20° C. The product is then recovered as described above.

In another embodiment the present invention provides a crystalline formof Carvedilol phosphate salt, referred to herein as Form F2. Form F2 ischaracterized by an X-Ray powder diffraction pattern with peaks at about7.4, 7.9, 8.5, 8.9 and 11.1±0.2 degrees two theta. The Calculated X-raypowder diffraction pattern of Carvedilol phosphate salt Form F2 issubstantially depicted in FIG. 35. The structure was solved by directmethods for triclinic P-1 group with the unit cell parameters:a=13.281(3), b=14.315(3), c=16.406(4)Å, α=66.85(2), β=85.94(2)γ=65.44(4) [deg], and cell volume 2592.4(12) Å³. Form F2 is carvediloldihydrogen phosphate hemiethanolate.

Form F2 is prepared by dissolution of Carvedilol dihydrogen phosphate inethanol at elevated temperature, of about 25° C. to about refluxtemperature, preferably about 70° C., followed by cooling. Carvediloldihydrogen phosphate Form I can be used as starting material. Cooling ispreferably carried out in about one to about 10 days, preferably about 6days. A final temperature can be about 10° C. to about 30° C.,preferably about 20° C. The crystal form can then be recovered byconventional techniques.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, denominated Form L, characterized bydata selected from the group consisting of: X-ray powder diffractionreflections at about: 4.6, 7.5, 8.7, 11.6 and 15.6 degrees two theta±0.2 degrees two theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 156.6, 150.3 and 102.5±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 54.1,47.8 and 0.0±0.1 ppm. The lowest ppm resonance in the chemical shiftarea of 100 to 180 ppm is typically at about 102.5±1 ppm.

A typical powder x-ray diffractogram for Form L is shown in FIG. 13. Atypical solid-state ¹³C-NMR spectrum of Form L is shown in FIG. 14 andor 14 a.

Form L can also be characterized by any five peaks selected from thefollowing list of PXRD peaks at about: 4.6, 7.5, 8.7, 11.6 13.4, 15.6and 19.4±0.2 degrees two theta.

Form L can also be characterized by data selected from: X-ray powderdiffraction reflections at about: 4.6, 7.5, 8.7, 11.6 and 15.0 degreestwo theta ±0.2 degrees two theta.

Form L can also be characterized by data selected from: X-ray powderdiffraction reflections at about: 4.6, 7.5, 8.7, 15.0 and 22.9 degreestwo theta ±0.2 degrees two theta.

Form L can be further characterized by data selected from the groupconsisting of: X-ray powder diffraction reflections at about 13.4, 19.4,22.3, 22.9 and 23.3 degrees two-theta, ±0.2 degrees two-theta; asolid-state ¹³C-NMR spectrum having chemical shift resonances at about148.3, 139.2 and 112.4±0.2 ppm; and a solid-state ¹³C NMR spectrumhaving chemical shift differences between the lowest ppm resonance inthe chemical shift area of 100 to 180 ppm and another in the chemicalshift area of 100 to 180 ppm of 45.8, 36.7 and 9.9±0.1 ppm. The lowestppm resonance in the chemical shift area of 100 to 180 ppm is typicallyat about 102.5±1 ppm.

GC measurement of residual solvents of Form L gives about 137500 ppm ofdioxane. Form L is a dioxane solvate of carvedilol dihydrogen phosphate

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form L comprising: combining carvedilol,phosphoric acid and dioxane and precipitating carvedilol dihydrogenphosphate Form L from the reaction mixture. In this embodiment less thanabout 30 g of carvedilol dihydrogen phosphate and less than about 300 mldioxane are used.

Precipitation may also be obtained from a slurry of carvediloldihydrogen phosphate and dioxane.

Whenever precipitation occurs from a slurry of carvedilol, phosphoricacid and dioxane, the carvedilol and phosphoric acid are preferablypresent in a molar ratio of about 1:1.

The ingredients are preferably heated to reflux, and further maintainedfor about 12 hours.

The carvedilol dihydrogen phosphate may be recovered by any method knownto the skilled artisan. Preferably, the carvedilol dihydrogen phosphateis recovered from the mixture by filtration, and then dried underreduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form L1,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 4.6, 8.7, 11.6, 14.6 and 15.3degrees two theta ±0.2 degrees two theta; a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about 156.6, 150.3 and 148.4±0.2ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 53.2, 46.9 and 45.0±0.1 ppm. The lowest ppm resonance inthe chemical shift area of 100 to 180 ppm is typically at about 103.4±1ppm.

Form L1 has an X-ray powder diffractogram as substantially shown in FIG.15. Form L1 has a solid-state ¹³C NMR spectrum as substantially shown inFIG. 16 and or 16 a.

Form L1 can also be characterized by PXRD peaks at about: 4.6, 7.4, 8.7,11.6 14.6, 15.3 and 19.4±0.2 degrees two theta.

Form L1 can also be characterized by PXRD peaks at about 4.6, 7.4, 8.7,13.6 and 15.3 degrees two theta ±0.2 degrees two theta.

Form L1 can also be characterized by PXRD peaks at about 4.6, 7.4, 8.7,11.6 and 17.4.

Form L1 can also be characterized by PXRD peaks at about 4.6, 7.4, 8.7,15.3 and 17.4 degrees two theta ±0.2 degrees two theta.

Form L1 can be further characterized by data selected from the groupconsisting of: X-ray powder diffraction reflections at about 7.4, 13.6,21.3 and 28.4 degrees two-theta, ±0.2 degrees two-theta; a solid-state¹³C-NMR spectrum having chemical shift resonances at about 140.3, 139.1,123.5 and 112.5±0.2 ppm; and a solid-state ¹³C NMR spectrum havingchemical shift differences between the lowest ppm resonance in thechemical shift area of 100 to 180 ppm and another in the chemical shiftarea of 100 to 180 ppm of 36.9, 35.7 20.1 and 9.1±0.1 ppm. The lowestppm resonance in the chemical shift area of 100 to 180 ppm is typicallyat about 103.4±1 ppm.

A typical powder x-ray diffractogram for Form L1 is shown in FIG. 15. Atypical solid-state ¹³C-NMR spectrum of Form L1 is shown in FIG. 16 andor 16 a.

Form L1 has a weight loss, as measured by TGA, of about 9.7% by weight,while it has water content, as measured by KF, of about 0.4% by weight.Form L1 is a dioxane solvate of carvedilol dihydrogen phosphate.

Form L1 can be obtained by a scaled up version of the process forproducing Form L. Accordingly, the invention also encompasses a processfor preparing carvedilol dihydrogen phosphate Form L1 comprisingslurrying at least about 30 g carvedilol dihydrogen phosphate,preferably Form I, in at least about 300 ml dioxane. Preferably, theslurry is heated to reflux.

The carvedilol dihydrogen phosphate may be recovered by any method knownto the skilled artisan. Preferably, the carvedilol dihydrogen phosphateis recovered from the mixture by filtration, and then dried, preferablyat about 55° C., under reduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, denominated Form N, characterized bydata selected from the group consisting of: X-ray powder diffractionreflections at about: 6.0, 6.9, 15.2, 16.3 and 17.4 degrees two theta±0.2 degrees two theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 154.4, 146.9 and 138.4±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 52.9,45.4 and 36.9±0.1 ppm. The lowest ppm resonance in the chemical shiftarea of 100 to 180 ppm is typically at about 101.5±1 ppm; a solid-state¹³C-NMR spectrum having chemical shift resonances at about 154.4, 146.9,138.4 and 110.9±0.2 ppm; and a solid-state ¹³C NMR spectrum havingchemical shift differences between the lowest ppm resonance in thechemical shift area of 100 to 180 ppm and another in the chemical shiftarea of 100 to 180 ppm of about 52.9, 45.4, 36.9 and 9.4±0.1 ppm. Thelowest ppm resonance in the chemical shift area of 100 to 180 ppm istypically at about 101.5 ±1 ppm.

Form N has an X-ray powder diffractogram as substantially shown in FIGS.17 and 18. Form N also has a solid-state ¹³C NMR spectrum assubstantially shown in FIG. 19 and or 19 a.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form N,characterized by data selected from: X-ray powder diffractionreflections at about: 6.0, 6.9, 13.7 15.2 and 18.1 degrees two theta±0.2 degrees two theta.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form N,characterized by data selected from: X-ray powder diffractionreflections at about: 6.0, 6.9, 13.7, 15.2 and 17.4±0.2 degrees twotheta.

Form N can be further characterized by data selected from the groupconsisting of: X-ray powder diffraction reflections at about 18.1, 20.6,24.6 and 26.3 degrees two-theta, ±0.2 degrees two-theta; a solid-state¹³C-NMR spectrum having chemical shift resonances at about 141.3, 122.0and 110.9±0.2 ppm; and a solid-state ¹³C NMR spectrum having chemicalshift differences between the lowest ppm resonance in the chemical shiftarea of 100 to 180 ppm and another in the chemical shift area of 100 to180 ppm of about 39.8, 20.5 and 9.4±0.1 ppm. The lowest ppm resonance inthe chemical shift area of 100 to 180 ppm is typically at about 101.5±1ppm, or substantially as depicted in FIG. 19 a.

A typical powder x-ray diffractogram for Form N is shown in FIGS. 17 and18. A typical solid-state ¹³C-NMR spectrum of Form N is shown in FIGS.19 and 19 a.

Form N has a weight loss, as measured by TGA, of about 5.0-6.6% byweight, while it has water content, as measured by KF, between 4.7-6.9%by weight. This corresponds to carvedilol dihydrogen phosphatedihydrate.

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form N comprising exposing carvediloldihydrogen phosphate Form L to high relative humidity (e.g., greaterthan about 80%, greater than about 90%, greater than about 95% or about100% relative humidity), preferably for at least about 7 days.

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form N comprising exposing carvediloldihydrogen phosphate Form F1, L1 or R to high relative humidity (e.g.,greater than about 80%, greater than about 90%, greater than about 95%or about 100% relative humidity), preferably for at least about 7 days.

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form N comprising exposing amorphouscarvedilol dihydrogen phosphate to high relative humidity (e.g., greaterthan 80%, greater than 90%, greater than 95% or about 100% relativehumidity), preferably for about 7 days.

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form N comprising drying carvediloldihydrogen phosphate Form O. Preferably, carvedilol dihydrogen phosphateForm O is heated to a temperature of from about 30° C. to about 70° C.,more preferably to about 35° C., for a time sufficient to obtaincarvedilol dihydrogen phosphate Form N. Carvedilol dihydrogen phosphateForm O may be prepared as described below. As one skilled in the artwill appreciate, the time required to obtain carvedilol dihydrogenphosphate Form N will vary depending upon, among other factors, theamount of wet carvedilol dihydrogen phosphate Form O to be dried and thedrying temperature, and can be determined by taking periodic XRDs.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, denominated Form O, characterized byX-ray powder diffraction reflections at about: 6.1, 12.2, 12.9, 16.2 and18.0 degrees two theta ±0.2 degrees two theta. Form O can be furthercharacterized by X-ray powder diffraction reflections at about 20.1,23.0, 23.7, 24.5 and 26.5 degrees two-theta, ±0.2 degrees two-theta. Atypical powder x-ray diffractogram for Form O is shown in FIG. 20.

X-ray powder diffractogram of Form O is substantially shown in FIG. 20.

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form O comprising grinding the amorphousform of carvedilol dihydrogen phosphate in the presence of water, forabout 1-2 minutes.

Preferably, the amorphous form is ground in the presence of 2-3 drops ofwater. Preferably, about 2-3 drops of water per 200 mg of amorphous formis used.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form P,characterized by data selected from the group consisting of: X-raypowder diffraction reflections at about: 5.3, 10.4, 16.8, 26.0 and 31.8degrees two theta ±0.2 degrees two theta; a solid-state ¹³C-NMR spectrumhaving chemical shift resonances at about 154.7, 146.6 and 122.2±0.2ppm; and a solid-state ¹³C NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 54.7, 46.6 and 22.2±0.1 ppm. The lowest ppm resonance inthe chemical shift area of 100 to 180 ppm is typically at about 100.0±1ppm.

Form P has a X-ray powder diffractogram as substantially shown in FIG.21. Form P has a solid-state ¹³C NMR spectrum as substantially shown inFIGS. 22 and 22 a.

Form P can also be characterized by any five peaks selected from thefollowing list of PXRD peaks at about: 5.3, 10.4, 14.5, 16.8, 17.8, 26.0and 31.8±0.2 degrees two theta.

Form P can also be characterized by X-ray powder diffraction reflectionsat about: 5.3, 10.4, 15.2, 17.8 and 22.5 degrees two theta ±0.2 degreestwo theta.

Form P can also be characterized by X-ray powder diffraction reflectionsat about: 5.3, 14.5, 15.2, 16.8 and 17.3 degrees two theta ±0.2 degreestwo theta.

Form P can also be characterized by X-ray powder diffraction reflectionsat about: 5.3, 10.4, 14.5, 15.2 and 17.8 degrees two theta ±0.2 degreestwo theta.

Form P can also be characterized by X-ray powder diffraction reflectionsat about: 5.3, 14.5, 15.2, 17.8 and 20.1 degrees two theta ±0.2 degreestwo theta.

Form P can be further characterized by data selected from the groupconsisting of: X-ray powder diffraction reflections at about 14.5 and17.8 degrees two-theta, ±0.2 degrees two-theta; a solid-state ¹³C-NMRspectrum having chemical shift resonances at about 141.4, 139.9 and111.9±0.2 ppm; and a solid-state ¹³C-NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 41.4, 39.9 and 11.9±0.1 ppm. The lowest ppm resonance inthe chemical shift area of 100 to 180 ppm is typically at about 100.0±1ppm. A typical powder x-ray diffractogram for Form P is shown in FIG.21. A typical solid-state ¹³C-NMR spectrum of Form P is shown in FIG. 22and or 22 a.

Form P has a weight loss, as measured by TGA, of about 2.0% by weight,while it has water content, as measured by KF, of about 1.7% by weight.Form P is carvedilol dihydrogen phosphate hemihydrate.

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form P comprising slurrying amorphouscarvedilol dihydrogen phosphate in ethanol. Preferably, the reactionoccurs at room temperature.

The carvedilol dihydrogen phosphate may be recovered by any method knownto the skilled artisan. Preferably, the carvedilol dihydrogen phosphateis recovered from the mixture by filtration, and then dried underreduced pressure (<1 atmosphere).

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form R,characterized by data selected from: X-ray powder diffractionreflections at about: 5.8, 11.8, 16.8, 18.6 and 23.2 degrees two theta±0.2 degrees two theta; a solid-state ¹³C-NMR spectrum having chemicalshift resonances at about 153.7, 147.9 and 122.8±0.2 ppm; and asolid-state ¹³C NMR spectrum having chemical shift differences betweenthe lowest ppm resonance in the chemical shift area of 100 to 180 ppmand another in the chemical shift area of 100 to 180 ppm of about 51.0,45.2 and 20.1±0.1 ppm. The lowest ppm resonance in the chemical shiftarea of 100 to 180 ppm is typically at about 102.7±1 ppm.

Form R has an X-ray powder diffractogram as substantially shown in FIG.29. Form R has a solid-state ¹³C NMR spectrum as substantially shown inFIG. 30 and or 30 a.

Form R is also characterized by an X-ray powder diffraction reflectionsat about: 5.8, 11.8, 15.5, 16.2 and 18.6 degrees two theta ±0.2 degreestwo theta.

Form R is also characterized by X-ray powder diffraction reflections atabout: 5.8, 16.2, 18.6, 23.2 and 27.0 degrees two theta ±0.2 degrees twotheta.

Form R is also characterized by X-ray powder diffraction reflections atabout: 5.8, 16.2, 16.8, 19.9 and 25.4 degrees two theta ±0.2 degrees twotheta.

Form R can be further characterized by X-ray powder diffractionreflections at about 8.5, 23.5, 24.7 and 27.0 degrees two-theta, ±0.2degrees two-theta; a solid-state ¹³C-NMR spectrum having chemical shiftresonances at about 137.8 and 116.5±0.2 ppm; and a solid-state ¹³C NMRspectrum having chemical shift differences between the lowest ppmresonance in the chemical shift area of 100 to 180 ppm and another inthe chemical shift area of 100 to 180 ppm of about 35.1 and 13.8±0.1ppm. The lowest ppm resonance in the chemical shift area of 100 to 180ppm is typically at about 102.7±1 ppm. A typical powder x-raydiffractogram for Form R is shown in FIG. 29. A typical solid-state¹³C-NMR spectrum of Form R is shown in FIG. 30 and or 30 a.

Form R has a weight loss, as measured by GC measurement of residualsolvents between about 75,000-100,300 ppm of isopropanol. Hence, Form Ris isopropanol solvate of carvedilol dihydrogen phosphate.

Form R can be prepared by combining carvedilol base, isopropyl alcohol,and phosphoric acid to obtain a reaction mixture, followed byprecipitation and recovery of Form R. Carvedilol base and phosphoricacid may be present in a molar ratio of about 0.8:1 to about 1.2:1,preferably 1:1. The reaction mixture can be heated or left at roomtemperature. Heating can be carried out of about 40° C. to about 60° C.,such as about 55° C. The reaction mixture can be cooled to acceleratethe precipitation process. Cooling can be carried at about 0° C. toabout 20° C.

The product can be recovered by conventional techniques such asfiltration. The crystals can be dried at elevated temperature, and apressure of less than about 1 atmosphere.

Form R can also be prepared by slurrying carvedilol dihydrogenphosphate, such as amorphous, Form F1, Form N, in isopropanol. Theslurry can be maintained to obtain Form R, such as a bout of about 6hours to about 3 days. The product can be recovered and dried as above.

The present invention also provides crystalline form of Carvedilolphosphate salt, referred to herein as Form W. The X-ray powderdiffraction pattern of Carvedilol phosphate salt Form W is substantiallydepicted in FIG. 32. Form W may be identified by characteristic X-Raydiffraction peaks at 6.6, 9.7, 13.8, 15.7 and 17.1±0.2.

Form W can be prepared from Carvedilol dihydrogen phosphate form F1, byadding Form F1 to KH₂PO₄, followed by adjustion with a base, such as analkali or alkaline metal base, including sodium and potassium hydroxideto obtain a suspension. A suspension is obtained when the pH reachesabout 7. The suspension can be stirred at room temperature for asufficient time, such as about 12 hours to about 2 days. Form W can berecovered by conventional techniques.

In another embodiment, the invention encompasses a crystalline form ofcarvedilol dihydrogen phosphate, referred to herein as Form Y,characterized by X-ray powder diffraction reflections at about: 7.7,7.9, 9.1, 16.6 and 19.5 degrees two theta ±0.2 degrees two theta; X-raypowder diffraction reflections at about: 7.7, 8.5, 16.6, 19.5 and 20.3degrees two theta ±0.2 degrees two theta. Form Y can be furthercharacterized by X-ray powder diffraction reflections at about 8.5 and15.5 degrees two-theta, ±0.2 degrees two-theta. A typical powder x-raydiffractogram for Form Y is shown in FIG. 31.

In another embodiment, the invention encompasses a process for preparingcarvedilol dihydrogen phosphate Form Y comprising precipitation from aslurry of carvedilol, phosphoric acid and ethanol, wherein the slurry ismaintained for about 2 to 3 hours.

The carvedilol and phosphoric acid are preferably present in a molarratio of about 1:1.

Preferably, absolute ethanol is used.

Preferably, the ingredients are heated to reflux. Whether theingredients are heated, the process may further comprise cooling, toinduce precipitation.

The carvedilol dihydrogen phosphate may be recovered by any method knownto the skilled artisan. Preferably, the carvedilol dihydrogen phosphateis recovered from the mixture by filtration.

Each of Forms L, L1, N, P, O, F, F1, F2, R, Y and W contain less thancomprises less than about 20% crystalline carvedilol phosphate salts byweight, more preferably less than about 10% by weight, and even morepreferably less than about 5% by weight, and even more preferably lessthan 1% by weight. The presence of a particular crystalline carvedilolcan be determined by the presence of PXRD peaks characteristic ofcrystalline carvedilol phosphate salts.

In certain embodiments, each of Form L, L1, N, P, O, F, F1, F2, R, Y andW contains less than about 20%, less than about 10%, less than about 5%or less than about 1% by weight of Form I of carvedilol dihydrogenphosphate. In certain embodiments, each of Form L, L1, N, P, O, F, F1,F2, R, Y and W is provided as a solid material in which Form L, L1, N,P, O, F, F1, F2, R, Y and W represents about 80%, about 90%, about 95%,or about 99% by weight of the solid material.

In another embodiment, the invention encompasses essentially amorphousform of carvedilol dihydrogen phosphate characterized by data selectedfrom the group consisting of: a solid-state ¹³C-NMR spectrum havingbroad chemical shift resonances at about 154.6, 146.7 and 140.3±0.2 ppm;and a solid-state ¹³C-NMR spectrum having chemical shift differencesbetween the lowest ppm resonance in the chemical shift area of 100 to180 ppm and another in the chemical shift area of 100 to 180 ppm ofabout 54.2, 46.3 and 39.9±0.1 ppm; a solid-state ¹³C-NMR spectrum havingbroad chemical shift resonances at about 154.6, 146.7, 140.3 and100.4±0.2 ppm; and a solid-state ¹³C-NMR spectrum having chemical shiftdifferences between the lowest ppm resonance in the chemical shift areaof 100 to 180 ppm and another in the chemical shift area of 100 to 180ppm of about 54.2, 46.3, 39.9 and 0.0±0.1 ppm. The lowest ppm resonancein the chemical shift area of 100 to 180 ppm is typically at about100.4±1 ppm. X-ray diffractogram shown in FIG. 33, solid state ¹³C-NMRspectrum shown in FIG. 34 and or 34 a.

The essentially amorphous form of carvedilol dihydrogen phosphate can befurther characterized by data selected from the group consisting of: asolid-state ¹³C-NMR spectrum having chemical shift resonances, which arebroader than chemical shift resonances of a crystalline material, atabout 121.9 and 111.5±0.2 ppm; and a solid-state ¹³C NMR spectrum havingchemical shift differences between the lowest ppm resonance in thechemical shift area of 100 to 180 ppm and another in the chemical shiftarea of 100 to 180 ppm of about 21.5 and 11.1±0.1 ppm. The lowest ppmresonance in the chemical shift area of 100 to 180 ppm is typically atabout 100.4±1 ppm. A typical powder x-ray diffractogram for theamorphous form is shown in FIG. 33. A typical solid-state ¹³C-NMRspectrum of amorphous form of carvedilol dihydrogen phosphate is shownin FIG. 34 and or 34 a.

The above amorphous form of carvedilol dihydrogen phosphate issubstantially free of crystalline and is herein referred to as“carvedilol dihydrogen phosphate purely amorphous.” FIG. 33 or 34illustrates an XRPD pattern for this form, where the halo shape of thepattern illustrates the substantial absence of crystalline structure, bythe absence of sharp peaks.

The carvedilol dihydrogen phosphate essentially amorphous contains notless than about 50% by weight of amorphous carvedilol dihydrogenphosphate, preferably not less than about 60%, more preferably not lessthan about 70%, even more preferably not less than about 80% and mostpreferably not less than about 90% or 95% by weight of amorphouscarvedilol dihydrogen phosphate. In a certain embodiment, the carvediloldihydrogen phosphate purely amorphous contains not more than about 20%by weight of Form I of carvedilol dihydrogen phosphate, preferably notmore than about 10%, more preferably not more than about 5%, even morepreferably not more than about 1% by weight of Form I of carvediloldihydrogen phosphate.

The amount of crystallinity is quantified by methods known in the artlike “crystallinity index” available to most XRD softwares.

Generally, the detection of peaks of Form I in amorphous carvediloldihydrogen phosphate can be done by any method known to the skilledartisan.

For example, a person skilled in the art would know, when using XRD as amethod for detecting or quantifying peaks of Form I in amorphouscarvedilol dihydrogen phosphate, to select a peak or a number of peaksfrom the following list of peaks at about 7.0, 8.0, 9.2, 11.4, 16.0 and20.7±0.2 degrees two theta. The absence or presence or intensity of apeak or a number of peaks from the following list of peaks at about 7.0,8.0, 9.2, 11.4, 16.0 and 20.7 ±0.2 degrees two theta may be monitored ata scan rate slow enough, according to the common knowledge of theskilled in the art. The scan rate used may vary from instrument toinstrument, and sample preparation. A skilled artisan will know to useother accepted analytical methods such as solid-state NMR, Raman, IR todetect Form I in amorphous carvedilol dihydrogen phosphate.

The carvedilol dihydrogen phosphate purely amorphous of the presentinvention is a solid material in which the carvedilol dihydrogenphosphate purely amorphous represents about 80% by weight of the solidmaterial, more preferably about 90%, even more preferably about 95% andmost preferably 99% by weight of the solid material, wherein thedetection of crystalline percentage and/or amorphous percentage materialcan be calculated according to the common knowledge of the skilled inthe art, for example by XRPD, in which the detection of crystallinepercentage and/or amorphous percentage material is calculated by theratio of the integrated area under the crystalline peaks to the totalintegrated area.

In another embodiment, the invention encompasses a process for preparingan amorphous form of carvedilol dihydrogen phosphate comprisingdissolving carvedilol dihydrogen phosphate in a solvent selected fromthe group consisting of C₁-C₈ alcohols and mixtures of C₃₋₇ ketones withwater, followed by solvent removal.

Preferably, a carvedilol dihydrogen phosphate purely amorphous isobtained.

Preferably, the solvent is methanol or acetone. Whenever acetone is usedas the solvent, a ratio of acetone/water of 2:1 is preferably used andthe solvent is preferably removed by spray drying.

Removing the solvent can be performed using vacuum drying or spraydrying.

Vacuum drying broadly refers to processes involving removal of liquidmaterial from a solution or mixture under air pressure below atmosphericpressure. The process of the present invention may preferably employvacuum drying at a pressure of less than one atmosphere, such as lessthan about 100 mm Hg, more preferably less than about 40 mm Hg.

Alternatively, the solution may be spray dried.

The processes of the present invention may preferably employ spraydrying with an inlet temperature of above about 80° C., preferably fromabout 80° C. to about 160° C.

The spray drying may preferably be conducted with an outlet temperatureof below the inlet temperature, preferably from about 30° C. to about110° C., more preferably below about 40° C.

The drying gas used in the process of the present invention may be anysuitable gas, although inert gases such as nitrogen, nitrogen-enrichedair, and argon are preferred.

The carvedilol dihydrogen phosphate product produced by spray drying maybe recovered by techniques commonly used in the art, such as using acyclone or a filter.

The carvedilol hydrogen phosphate starting material used for theprocesses of the present invention may be any crystalline or amorphousform of carvedilol hydrogen phosphate, including any solvates andhydrates. With processes where carvedilol hydrogen phosphate goes intosolution, the form of the starting material is of minimal relevancesince any solid state structure is lost in solution.

Amorphous Carvedilol Dihydrogen phosphate can also be prepared byheating another crystalline form of Carvedilol Dihydrogen phosphate,Particularly, heating of crystalline forms Form N or R results inAmorphous Carvedilol Dihydrogen. Heating is carried out at a temperatureof about 80° C. to about 110° C. preferably about 80° C. to about 100°C. Heating can be carried out until the amorphous form obtained, such asfrom about 10 minutes to about 1 hours, preferably about 30 minutes.

Amorphous Carvedilol Dihydrogen phosphate can also be prepared byheating another crystalline form of Carvedilol Dihydrogen phosphate,Particularly, heating of crystalline Form N results in AmorphousCarvedilol Dihydrogen. Heating is preferably carried out at atemperature of about 20° C. to about 150° C., preferably about 140° C.Heating can be carried out until the amorphous form obtained, such asfrom about 10 minutes to about 4 hours, preferably about 30 minutes. Inanother embodiment, the invention encompasses a process for preparing amixture of carvedilol dihydrogen phosphate Form N and carvediloldihydrogen phosphate Form I comprising dissolving carvedilol dihydrogenphosphate in a mixture of C₃₋₇ ketones with water, followed by vacuumdrying.

Preferably, the solvent is acetone. Whenever acetone is used as thesolvent, a ratio of acetone/water of 2:1 is preferably used.

The invention further encompasses pharmaceutical compositions comprisingthe crystalline carvedilol phosphate, carvedilol hydrogen phosphate andcarvedilol dihydrogen phosphate of the invention and, optionally,amorphous carvedilol dihydrogen phosphate of the invention, and at leastone pharmaceutically acceptable excipient.

Pharmaceutical compositions of the invention contain the carvediloldihydrogen forms of the invention, optionally in mixture with othercrystalline or amorphous forms of carvedilol and/or other activeingredients such as hydrochlorothiazide.

In certain embodiments, the pharmaceutical compositions of the inventioncomprise Form L1 Form N, Form P, Form F, Form F1, Form F2, Form R, FormY, Form L, Form L1, Form G, Form H, Form K, Form Q, Form Y or Form W andless than about 50%, less than about 25%, less than about 10%, less thanabout 5%, or less than about 1% (by weight of Form I of carvediloldihydrogen phosphate present).

In certain embodiments, the pharmaceutical compositions of the inventioncomprise amorphous carvedilol phosphate and less than about 50%, lessthan about 25%, less than about 10%, less than about 5%, or less thanabout 1% (by weight of Form I of carvedilol dihydrogen phosphatepresent).

In certain embodiments, the pharmaceutical compositions of the inventioncomprise amorphous carvedilol hydrogen phosphate and less than about50%, less than about 25%, less than about 10%, less than about 5%, orless than about 1% (by weight of Form I of carvedilol dihydrogenphosphate present).

In certain embodiments, the pharmaceutical compositions of the inventioncomprise amorphous carvedilol dihydrogen phosphate and less than about50%, less than about 25%, less than about 10%, less than about 5%, orless than about 1% (by weight of Form I of carvedilol dihydrogenphosphate present).

In certain embodiments, the pharmaceutical compositions of the inventioncomprise a therapeutically effective amount of carvedilol phosphate,carvedilol hydrogen phosphate and carvedilol dihydrogen phosphatecrystalline forms G, H, K, Q, L, L1, N, O, P, F, F1, F2, R, Y, W andamorphous forms (1:1, 2:1, 3:1) or mixtures thereof.

The purity of carvedilol phosphate, carvedilol hydrogen phosphate andcarvedilol dihydrogen phosphate crystalline forms G, H, K, Q, L, L1, N,O, P, F, F1, F2, R, Y, W and amorphous form can be measured by anyperson skilled in the art, by PXRD using at least one peak of Form Iwhen measuring the content of Form I. The peak or peaks may be selectedfrom the following list of peaks at about: 7.0, 8.0, 9.2, 11.4, 14.0,14.8, 15.5, 16.0, 18.3, 18.9, 19.7, 22.3, 22.9 and 25.4±0.2 degrees twotheta.

Alternatively, the purity of the above crystalline forms can be measuredby solid-state ¹³C NMR using at list one signal of Form I when measuringthe content of Form I. The signal or signals may be selected from thefollowing list of signals at about: 154.5, 146.5, 141.1, 139.7, 125.3,122.1, 120.7, 118.3, 113.6, 110.2, 109.4 and 103.8±0.2 ppm.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising by at least about 95% by weight at least one ofthe following crystal forms: crystalline Form G of carvedilol hydrogenphosphate, crystalline Form H of carvedilol hydrogen phosphate,crystalline Form K of carvedilol hydrogen phosphate, crystalline Form Qof carvedilol hydrogen phosphate crystalline Form L of carvediloldihydrogen phosphate, crystalline Form L1 of carvedilol dihydrogenphosphate, crystalline Form N of carvedilol dihydrogen phosphate,crystalline Form O of carvedilol dihydrogen phosphate, crystalline FormP of carvedilol dihydrogen phosphate, crystalline Form F of carvediloldihydrogen phosphate, crystalline Form F1 of carvedilol dihydrogenphosphate, crystalline Form F2 of carvedilol dihydrogen phosphate,crystalline Form R of carvedilol dihydrogen phosphate, crystalline FormY of carvedilol dihydrogen phosphate,- and a pharmaceutically acceptableexcipient, crystalline Form W of carvedilol dihydrogen phosphate.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of crystallineForm G of carvedilol hydrogen phosphate, crystalline Form H ofcarvedilol hydrogen phosphate, crystalline Form K of carvedilol hydrogenphosphate, crystalline Form Q of carvedilol hydrogen phosphatecrystalline Form L of carvedilol dihydrogen phosphate, crystalline FormL1 of carvedilol dihydrogen phosphate, crystalline Form N of carvediloldihydrogen phosphate, crystalline Form O of carvedilol dihydrogenphosphate, crystalline Form P of carvedilol dihydrogen phosphate,crystalline Form F of carvedilol dihydrogen phosphate, crystalline FormF1 of carvedilol dihydrogen phosphate, crystalline Form F2 of carvediloldihydrogen phosphate, crystalline Form R of carvedilol dihydrogenphosphate, crystalline Form Y of carvedilol dihydrogen phosphate,- and apharmaceutically acceptable excipient, crystalline Form W of carvediloldihydrogen phosphate, amorphous carvedilol phosphate and amorphouscarvedilol dihydrogen phosphate, and a pharmaceutically acceptableexcipient.

In another embodiment, the present invention provides a method oftreatment of congestive heart failure or hypertension comprisingadministering the above pharmaceutical composition to a mammal in needthereof.

Another embodiment of the invention provides a process of preparing apharmaceutical composition comprising combining any of the carvediloldihydrogen phosphate, carvedilol hydrogen phosphate and carvedilolphosphate forms of the invention, or a solution prepared using thecarvedilol dihydrogen phosphate forms of the invention, with at leastone pharmaceutically acceptable excipient.

Pharmaceutical compositions of the invention can contain the amorphousforms and/or crystalline forms of carvedilol phosphate, carvedilolhydrogen phosphate, or carvedilol dihydrogen phosphate described herein,optionally in mixture with other active ingredients such ashydrochlorothiazide. In addition to the active ingredient(s), thepharmaceutical compositions of the present invention can contain one ormore excipients. Excipients are added to the composition for a varietyof purposes.

Diluents increase the bulk of a solid pharmaceutical composition and canmake a pharmaceutical dosage form containing the composition easier forthe patient and caregiver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. AVICEL®),microfine cellulose, lactose, starch, pregelatinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. EUDRAGIT®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage formlike a tablet can include excipients whose functions include helping tobind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions include atleast one of acacia, alginic acid, carbomer (e.g. carbopol),carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guargum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropylcellulose (e.g. KLUCEL®), hydroxypropyl methyl cellulose (e.g.METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin,methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON®,PLASDONE®), pregelatinized starch, sodium alginate, or starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach can be increased by the addition of a disintegrantto the composition. Disintegrants include, but are not limited to,alginic acid, carboxymethylcellulose calcium, carboxymethylcellulosesodium (e.g. AC-DI-SOL@PRIMELLOSE®), colloidal silicon dioxide,croscarmellose sodium, crospovidone (e.g. KOLLIDON®, POLYPLASDONE®),guar gum, magnesium aluminum silicate, methyl cellulose,microcrystalline cellulose, polacrilin potassium, powdered cellulose,pregelatinized starch, sodium alginate, sodium starch glycolate (e.g.EXPLOTAB®) or starch.

Glidants can be added to improve the flow properties of non-compactedsolid composition and improve the accuracy of dosing. Excipients thatcan function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc, and/or tribasic calciumphosphate.

When a dosage form such as a tablet is made by compaction of a powderedcomposition, the composition is subjected to pressure from a punch anddye. Some excipients and active ingredients have a tendency to adhere tothe surfaces of the punch and dye, which can cause the product to havepitting and other surface irregularities. A lubricant can be added tothe composition to reduce adhesion and ease release of the product formthe dye. Lubricants include, but are not limited to, magnesium stearate,calcium stearate, glyceryl monostearate, glyceryl palmitostearate,hydrogenated castor oil, hydrogenated vegetable oil, mineral oil,polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodiumstearyl fumarate, stearic acid, talc, and/or zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that can be included in the composition ofthe present invention include, but are not limited to, maltol, vanillin,ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, ortartaric acid.

Solid and liquid compositions can also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention, one ormore of the carvedilol forms described above and any other solidexcipients are dissolved or suspended in a liquid carrier such as water,vegetable oil, alcohol, polyethylene glycol, propylene glycol orglycerin.

Liquid pharmaceutical compositions can contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that can be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol, or cetyl alcohol.

Liquid pharmaceutical compositions of the present invention can alsocontain a viscosity-enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch, tragacanthor xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and/or invert sugar can be addedto improve the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid can be added at levels safe for ingestion to improvestorage stability.

A liquid composition according to the invention can also contain abuffer such as gluconic acid, lactic acid, citric acid or acetic acid,sodium gluconate, sodium lactate, sodium citrate or sodium acetate.

Selection of excipients and the amounts to use can be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the invention include powders, granulates,aggregates and compacted compositions.

The amorphous forms and/or crystalline forms of carvedilol phosphate,carvedilol hydrogen phosphate, or carvedilol dihydrogen phosphate of theinvention can be administered for treatment of congestive heart failureand hypertension (by any means that delivers the active ingredients) tothe site of the body where beta-blocking activity exerts a therapeuticeffect on the patient. For example, administration can be oral, buccal,parenteral (including subcutaneous, intramuscular, and intravenous)rectal, inhalant or ophthalmic. Although the most suitable route in anygiven case will depend on the nature and severity of the condition beingtreated, the most preferred route of the invention is oral. Amorphouscarvedilol phosphate of the invention can be conveniently administeredto a patient in oral unit dosage form and prepared by any of the methodswell-known in the pharmaceutical arts. Dosage forms include solid dosageforms like tablets, powders, capsules, sachets, troches, or lozenges aswell as liquid syrups, suspensions, or elixirs.

The active ingredient(s) and excipients can be formulated intocompositions and dosage forms according to methods known in the art.

A composition for tableting or capsule filling can be prepared by wetgranulation. In wet granulation some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water that causes the powders to clumpup into granules. The granulate is screened and/or milled, dried andthen screened and/or milled to the desired particle size. The granulatecan then be tableted or other excipients can be added prior to tabletingsuch as a glidant and or lubricant.

A tableting composition can be prepared conventionally by dry blending.For instance, the blended composition of the actives and excipients canbe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules can be compressed subsequently into atablet.

As an alternative to dry granulation, a blended composition can becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suited todirect compression tableting include microcrystalline cellulose, spraydried lactose, dicalcium phosphate dihydrate and/or colloidal silica.The proper use of these and other excipients in direct compressiontableting is known to those in the art with experience and skill inparticular formulation challenges of direct compression tableting.

A capsule filling of the invention can comprise any of theaforementioned blends and granulates that were described with referenceto tableting, only they are not subjected to a final tableting step.

Yet more particularly, a tablet can, for example, be formulated byblending and directly compressing the composition in a tablet machine.

A capsule can, for example, be prepared by filling half of a gelatincapsule with the above tablet composition and capping it with the otherhalf of the gelatin capsule.

A simple parenteral solution for injection can, for example, be preparedby combining amorphous carvedilol phosphate of the invention, sterilepropylene glycol, and sterile water and sealing the composition in asterile vial under sterile conditions.

Capsules, tablets and lozenges and other unit dosage forms preferablycontain a dosage level of about 1 mg to about 100 mg of amorphous formsand/or crystalline forms of carvedilol phosphate, carvedilol hydrogenphosphate, or carvedilol dihydrogen phosphate described herein.

Another embodiment of the present invention provides a method fortreating a patient suffering from hypertension, congestive heartfailure, or another condition that would benefit from treatment withamorphous forms and/or crystalline forms of carvedilol phosphate,carvedilol hydrogen phosphate, or carvedilol dihydrogen phosphate,comprising the step of administering to the patient a pharmaceuticalcomposition comprising a therapeutically effective amount of theamorphous forms and/or crystalline forms of carvedilol phosphate,carvedilol hydrogen phosphate, or carvedilol dihydrogen phosphate of theinvention described herein.

The amorphous form (1:1) of the present invention has higher solubilitywith compared to Form I at pH=7 and 25° C.:

Form Solubility (μg/mL) I (′027) 9.6 Amorphous 14.9Such higher solubility contributes to better bioavailability and canlead to greater efficacy. Furthermore, the amorphous form has veryhomogenous spherical habit (FIG. 52) directly obtained from manufactureprocess with compared to Form I (FIG. 36) or Form IV (FIG. 37).Pharmaceutical particles are rarely spherical. Such spherical habit hasmany advantages such as: higher compressibility. The compressibility andhomogeneity of the powder also affect the uniformity of the solid dosageform (poor content uniformity would result if a drug powder were notdispersed evenly throughout a mixture with excipients) and its size.

Using spherical powders, flowability of the powder may be improved.Processing of powders strongly depends on powder flowability. Powderflowability is defined as the time required for a specific quantity ofpowder to flow through an orifice or a die cavity. Flowability of apowder is important in high-volume manufacturing, which depends onrapid, uniform, consistent filling of die cavity. Poor flowcharacteristics cause slow and nonuniform press feeding and difficultyin ensuring a fill of the die cavity. Free-flowing powder refers topowders that readily flow in the die cavity [ASM Handbook, vol. 7:Powder Metallurgy].

Forms F, F1, L, L1, N, P and R of the present invention have morecrystallinity than Form I (about 86% for Form R, about 87% for Form F,about 86% for F1, about 88% for L and about 85% for L1 compared to about68% of I, about 86% for Form N, about 85% for Form P) as can be seenfrom the % crystallinity calculation preformed using the WinXRD 2.0program (FIGS. 46, 48, 39, 40, 43, 53, 50, 41). Less crystallinitypowder means that the % of the amorphous ratio of the powder is greater,which can mean less stable material (amorphous materials are chemicallyand physically less stable than crystalline materials, such as whenexposed to pressure, grinding, heat, long term shelf-life, humidity,etc.)

Forms F, F1, L, L1 and R are more stable for formulation than Form IV.Under extreme heat conditions (80° C. for 30 min in oven) which may beused during formulation processes, Forms F, F1, L, L1 and R are stableupon heating when compared to Form IV (it transforms to amorphous formunder these conditions).

Forms F, F1, N and Y of the present invention have bigger particle sizedimensions (Form N has particle size dimensions ˜200-400 μm) (Form Y hasbigger particle size dimensions ˜20-100 μm), (Form F1 has particle sizedimensions ˜50-150 μm) (Form F has bigger particle size dimensions˜50-200 μm) compared to Form I (less than 20 μm), as can be seen fromthe microscope images of FIGS. 45, 47, 42, 51, 38. It has the advantageof being able to reduce the particle size to a range of smallerdimensions (according to the requirements of the formulator who preparethe capsule or tablet), while when starting in advance with a smallersize of powder (Form I) limits this option. In addition, smallparticles, reduce flowability.

Form P has higher melting point (about 158° C.) with compared to Form IV(about 90° C.) as was measured by DSC (Differential ScanningCalorimetry) measurement which is a thermal analysis technique to detectheat changes of a material as a function of temperature change.

Form Y has a more homogenous habit (FIG. 51) directly obtained frommanufacture process when compared to that of Form IV (FIG. 44). This hasmany advantages such as: higher compressibility which is very importantfor handling the powder, storage, safety, etc. The compressibility andhomogeneity of the powder also affect the uniformity of the solid dosageform (poor content uniformity would result if a drug powder were notdispersed evenly throughout a mixture with excipients) and its size.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther defined by reference to the following examples describing indetail the preparation of the composition and methods of use of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

The following examples are given for the purpose of illustrating theinvention and shall not be construed as limiting the scope or spirit ofthe invention.

EXAMPLES Instruments

Powder X-Ray Diffraction

Powder X-ray diffraction data were obtained by using conventionalmethods employing a SCINTAG powder X-Ray diffractometer model X'TRAequipped with a solid-state detector. Copper radiation of 1.5418 Å wasused to analyze the samples, which were in round aluminum sample holderswith zero background. All peak positions reported are within ±0.2degrees two theta.

TGA Analysis

TGA analysis was preformed using Mettler 3M with Mettler TG 50thermobalance. The weight of the samples was about 10 mg; the sampleswere scanned at a rate of 10° C./min from 25° C. to 200 or 250° C. Theoven was constantly purged with nitrogen gas at a flow rate of 40ml/min. Standard alumina crucibles covered by lids with 1 hole wereused.

Water Content

Water content was determined by Karl Fisher analysis using MettlerToledo DL 38 Karl Fisher Titrator.

¹³C NMR Spectroscopy

The cp/mas ¹³C NMR investigations were preformed at 125.76 MHz atambient temperature on a Bruker DMX-500 digital FT-NMR spectrometerequipped with a BL-4 cp/mas probehead and High Resolution/HighPerformance (HPHP) 1H and X-channel preamplifiers for solids. Sampleswere placed in 4 mm zirconia rotors fitted with ‘Kel-F’ plastic caps,and spun with dry air at 5.0 kHz.

Example 1 Preparation of Amorphous Carvedilol Phosphate

To a mixture of 3 g of carvedilol in 45 ml ethanol was slowly added 0.14ml of phosphoric acid. The mixture was heated to reflux until completedissolution. The resulting solution was stirred for an additional 10minutes, and cooled to room temperature. 45 ml of water were then addedto the solution and it was stirred overnight, upon which a precipitateformed. The precipitate was filtered and dried in a vacuum oven to give2.7 g of a white solid. The resulting solid was analyzed by PXRD and wasdetermined to be amorphous carvedilol phosphate.

Example 2 Preparation of Carvedilol Hydrogen Phosphate Form G

To a mixture of 5 g of carvedilol in 50 ml methyl alcohol was slowlyadded 0.84 ml of phosphoric acid and the mixture heated to reflux toobtain a clear solution. After cooling to room temperature, 50 ml ofwater were added and the resulting solid was filtered and dried in avacuum oven to give 2.85 g of a white solid. The resulting solid wasanalyzed by XRD and shown to be carvedilol hydrogen phosphate Form G.

Example 3 Preparation of Carvedilol Hydrogen Phosphate Form G

To a mixture of 3 g of carvedilol in 45 ml acetone/water (3:1) wasslowly added 0.22 ml of phosphoric acid and the mixture was stirredovernight at room temperature. The resulting solid was filtered andanalyzed by XRD and shown to be carvedilol hydrogen phosphate Form G.

Example 4 Preparation of Phosphate Salt of Carvedilol Hydrogen PhosphateForm G

10 g of dry amorphous carvedilol dihydrogen phosphate were charged into1 liter glass reactor equipped with mechanical stirrer, and controlledheating/cooling system. 250 ml of 0.1M (buffer phosphoric pH=3.5)aqueous solution were charged into the reactor. The agitator was turnedon, and suspension was obtained. The suspension was stirred at 25° C.for 19 hours and filtered.

The cake product was dried in a vacuum oven under a reduced pressure(under 100 mmHg) at 50° C. until a dried product was obtained.

The resulting solid was analyzed by XRD and showed phosphate salt ofcarvedilol hydrogen phosphate Form G.

Example 5 Preparation of Phosphate Salt of Carvedilol Hydrogen PhosphateForm G

10 g of dry amorphous carvedilol dihydrogen phosphate were charged into1 liter glass reactor equipped with mechanical stirrer, and controlledheating/cooling system. 250 ml of 0.1M (buffer phosphoric pH=7) aqueoussolution were charged into the reactor. The agitator was turned on, andsuspension was obtained. The suspension was stirred at 25° C. for 21hours and filtered.

The cake product was dried in a Vacuum oven under a reduced pressure(under 100 mmHg) at 50° C. until a dried product was obtained.

The resulting solid was analyzed by XRD and showed phosphate salt ofcarvedilol hydrogen phosphate Form G.

Example 6 Preparation of Carvedilol Hydrogen Phosphate Form G

A 50 ml flask is charged with 1 g of Carvedilol dihydrogen phosphateForm R and 10 ml water. The mixture is stirred at room temperature for24 hours until the crystals are converted to Form G. The crystals arecollected by filtration under reduced pressure and dried at 50° C. underreduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed Carvedilol hydrogenphosphate Form G.

Example 7 Preparation of Carvedilol Hydrogen Phosphate Form G

A 50 ml flask is charged with 1 g of Carvedilol dihydrogen phosphateForm F1 and 10 ml water. The mixture is stirred at room temperature for24 hours until the crystals are converted to Form G. The crystals arecollected by filtration under reduced pressure and dried at 50° C. underreduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed Carvedilol hydrogenphosphate Form G.

Example 8 Preparation of Carvedilol Hydrogen Phosphate Form H

To a mixture of 3 g of carvedilol in 45 ml ethyl alcohol was slowlyadded 0.22 ml of phosphoric acid and the mixture heated to reflux and150 ml of ethyl alcohol followed by 30 ml of water were added. Aftercooling to room temperature, the mixture was stirred overnight. Theresulting solid was filtered and dried in a vacuum oven to give 2.37 gof a white solid. The resulting solid was analyzed by XRD and shown tobe carvedilol hydrogen phosphate Form H.

Example 9 Preparation of Carvedilol Hydrogen Phosphate Form K

Carvedilol hydrogen phosphate Form H was exposed to 80% and 100%relative humidity (RH) for 16 days at room temperature. According toXRD, the exposed samples contain carvedilol hydrogen phosphate Form K.

Example 10 Preparation of Carvedilol Hydrogen Phosphate Form K

A mixture of 10 g of carvedilol in 150 ml acetone/water (3:1) wasstirred at room temperature for 30 minutes and 0.56 ml. of phosphoricacid 85% were added and stirred for overnight. The resulting mixture wasfiltered and dried in vacuum oven for over night at 50° C. The productwas analyzed by XRD and found to be carvedilol hydrogen phosphate FormK.

Example 11 Preparation of a Mixture of Carvedilol Hydrogen PhosphateForms K and H

A mixture of 10 g of carvedilol in 150 ml acetone/water (3:1) wasstirred at room temperature for 30 minutes and filtrated (to removeforeign objects). To the filtrated solution was added 0.56 ml. ofphosphoric acid 85% and stirred for overnight. The resulting mixture wasfiltered and dried in vacuum oven for over night at 50° C. The productwas analyzed by XRD and found to be a mixture of carvedilol hydrogenphosphate Forms K and H.

Example 12 Preparation of carvedilol hydrogen phosphate Form Q

Carvedilol hydrogen phosphate Form K was exposed to 0% relative humidity(RH) for 7 days at room temperature. According to XRD, the exposedsample is carvedilol hydrogen phosphate Form Q.

Example 13 Preparation of Amorphous Carvedilol Hydrogen Phosphate

10 g of carvedilol hydrogen phosphate was dissolved in 200 ml ofmethanol at reflux. The solution was sprayed (72 [ml/h]) into thechamber with ambient nitrogen (38 m³/h, 100° C.) at co-current flow. Theatomizing flow (660[l/h]) of nitrogen produced droplets, which led to ahigh evaporation rate. The temperature of the outlet solids was 29-30°C. The obtained sample was analyzed by XRD and found to be amorphouscarvedilol hydrogen phosphate.

Example 14 Preparation of Amorphous Carvedilol Hydrogen Phosphate

10 g of carvedilol hydrogen phosphate was dissolved in 200 ml ofacetone/water (2:1) at reflux. The solution was sprayed (72 [ml/h]) intothe chamber with ambient nitrogen (38 m³/h, 100° C.) at co-current flow.The atomizing flow (660[l/h]) of nitrogen produced droplets, which ledto a high evaporation rate. The temperature of the outlet solids was 40°C. The obtained sample was analyzed by XRD and found to be amorphous.

Example 15 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 100 ml acetone was slowly added0.84 ml of phosphoric acid and the mixture stirred at the sametemperature overnight. The resulting solid was filtered and dried in avacuum oven to give 2.46 g of a white solid. The resulting solid wasanalyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.

Example 16 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 75 ml ethanol was slowly added 0.84ml of phosphoric acid and the mixture was heated to reflux. The mixturewas cooled to room temperature and kept at the same temperatureovernight. The resulting solid was filtered and dried in a vacuum ovento give 5.22 g of a white solid. The resulting solid was analyzed by XRDand showed Carvedilol dihydrogen phosphate Form I.

Example 17 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 120 ml IPA was slowly added 0.84 mlof phosphoric acid and the mixture was heated to reflux. After 1 hour,the mixture was cooled to room temperature and stirred overnight. Theresulting solid was filtered and dried in a vacuum oven to give 5.12 gof a white solid. The resulting solid was analyzed by XRD and showedCarvedilol dihydrogen phosphate Form I.

Example 18 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 3 g of Carvedilol in 45 ml ethanol was slowly added 0.53ml of phosphoric acid and the mixture was heated to reflux. To thereflux mixture were added an additional 150 ml of ethanol and 30 ml ofwater (till complete dissolution). After cooling to room temperature,the mixture was stirred overnight. The resulting solid was filtered anddried in a vacuum oven to give 2.32 g of a white solid. The resultingsolid was analyzed by XRD and showed Carvedilol dihydrogen phosphateForm I.

Example 19 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 50 ml methanol was slowly added0.84 ml of phosphoric acid and the mixture was heated to reflux (tillcomplete dissolution). After cooling to room temperature, 20 ml of waterwere added and the mixture stirred at the same temperature overnight.The resulting solid was filtered and dried in a vacuum oven to give 4.06g of a white solid. The resulting solid was analyzed by XRD and showedCarvedilol dihydrogen phosphate Form I.

Example 20 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 75 ml ethanol was slowly added 0.84ml of phosphoric acid and the mixture was heated to reflux and 75 ml ofwater was added (till complete dissolution). The solution was cooled toroom temperature and stirred at the same temperature overnight. Theresulting solid was filtered and dried in a vacuum oven to give 4 g of awhite solid. The resulting solid was analyzed by XRD and showedCarvedilol dihydrogen phosphate Form I.

Example 21 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 25 ml THF was slowly added 0.84 mlof phosphoric acid and stirred at room temperature overnight. Theresulting solid was filtered and dried in a vacuum oven to give 6 g of awhite solid. The resulting solid was analyzed by XRD and showedCarvedilol dihydrogen phosphate Form I.

Example 22 Preparation of Carvedilol Dihydrogen Phosphate Form I

A slurry of 1 g of a mixture of Carvedilol hydrogen phosphate andCarvedilol base in 10 ml acetone was stirred overnight. The resultingsolid was filtered and dried in a vacuum oven to give 0.27 g of a whitesolid. The resulting solid was analyzed by XRD and showed Carvediloldihydrogen phosphate Form I content.

Example 23 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 10 g of Carvedilol in 200 ml absolute ethanol was slowlyadded 1.7 ml of phosphoric acid and 100 ml of ethanol were slowlydistilled out. The solution was cooled to room temperature and stirredat the same temperature overnight. The resulting solid was filtered anddried in a vacuum oven to give 7 g of a white solid. The resulting solidwas analyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.

Example 24 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 50 ml acetonitrile was slowly added0.84 ml of phosphoric acid and the mixture was heated to reflux. Thesolution was cooled to room temperature and stirred at the sametemperature for overnight. The resulting solid was filtered and dried ina vacuum oven to give 3.36 g of a white solid. The resulting solid wasanalyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.

Example 25 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 100 ml heptane was slowly added0.84 ml of phosphoric acid and the mixture was heated to reflux. Themixture was cooled to room temperature and stirred at the sametemperature overnight. The resulting solid was filtered and dried in avacuum oven to give 2.12 g of a white solid. The resulting solid wasanalyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.

Example 26 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 50 ml PGME was slowly added 0.84 mlof phosphoric acid and the mixture was heated to reflux. The solutionwas cooled to room temperature and stirred at the same temperatureovernight. The resulting solid was filtered and dried in a vacuum ovento give 5.17 g of a white solid. The resulting solid was analyzed by XRDto yield Carvedilol dihydrogen phosphate Form I.

Example 27 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 100 ml MIBK was slowly added 0.84ml of phosphoric acid and the mixture was heated to reflux. The mixturewas cooled to room temperature and stirred at the same temperatureovernight. The resulting solid was filtered and dried in a vacuum ovento give 0.66 g of a white solid. The resulting solid was analyzed by XRDto yield Carvedilol dihydrogen phosphate Form I.

Example 28 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 100 ml MEK was slowly added 0.84 mlof phosphoric acid and the mixture was heated to reflux. The mixture wascooled to room temperature and stirred at the same temperatureovernight. The resulting solid was filtered and dried in a vacuum ovento give 5.65 g of a white solid. The resulting solid was analyzed by XRDto yield Carvedilol dihydrogen phosphate Form I.

Example 29 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 50 ml 2-BuOH was slowly added 0.84ml of phosphoric acid and the mixture was heated to reflux. The solutionwas cooled to room temperature and stirred at the same temperatureovernight. The resulting solid was filtered and dried in a vacuum ovento give 3.89 g of a white solid. The resulting solid was analyzed by XRDto yield Carvedilol dihydrogen phosphate Form I.

Example 30 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 50 ml n-BuOH was slowly added 0.84ml of phosphoric acid and the mixture was heated to reflux. The solutionwas cooled to room temperature and stirred at the same temperature for 5hours. The resulting solid was filtered and dried in a vacuum oven togive 0.30 g of a white solid. The resulting solid was analyzed by XRD toyield Carvedilol dihydrogen phosphate Form I.

Example 31 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 5 g of Carvedilol in 150 ml tert-BuOH was slowly added0.84 ml of phosphoric acid and the mixture was heated to reflux. Themixture was cooled to room temperature and stirred at the sametemperature over the weekend. The resulting solid was filtered and driedin a vacuum oven to give 2.74 g of a white solid. The resulting solidwas analyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.

Example 32 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 8 g of Carvedilol in 80 ml n-propanol was slowly added1.34 ml of phosphoric acid and the mixture stirred at room temperatureovernight. The resulting solid was filtered and dried in a vacuum ovento give 5.67 g of a white solid. The resulting solid was analyzed by XRDand showed Carvedilol dihydrogen phosphate Form I.

Example 33 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 8 g of Carvedilol in 80 ml of methyl acetate was slowlyadded 1.34 ml of phosphoric acid and the mixture stirred at roomtemperature overnight. The resulting solid was filtered and dried in avacuum oven to give 5.13 g of a white solid. The resulting solid wasanalyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.

Example 34 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 8 g of Carvedilol in 80 ml isobutyl acetate was slowlyadded 1.34 ml of phosphoric acid and the mixture was heated to reflux.After 2 hour, the mixture was cooled to room temperature and stirredovernight. The resulting solid was filtered and dried in a vacuum ovento give 7.5 g of a white solid. The resulting solid was analyzed by XRDand showed Carvedilol dihydrogen phosphate Form I.

Example 35 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 8 g of Carvedilol in 80 ml ethyl acetate was slowlyadded 1.34 ml of phosphoric acid and the mixture was heated to reflux.After 2 hour, the mixture was cooled to room temperature and stirredovernight. The resulting solid was filtered and dried in a vacuum ovento give 7.2 g of a white solid. The resulting solid was analyzed by XRDand showed Carvedilol dihydrogen phosphate Form I.

Example 36 Preparation of Carvedilol Dihydrogen Phosphate Form I

To a mixture of 8 g of Carvedilol in 80 ml MTBE was slowly added 1.34 mlof phosphoric acid and the mixture was heated to reflux. After 2 hour,the mixture was cooled to room temperature and stirred overnight. Theresulting solid was filtered and dried in a vacuum oven to give 7.7 g ofa white solid. The resulting solid was analyzed by XRD and showedCarvedilol dihydrogen phosphate Form I.

Example 37 Preparation of Carvedilol Dihydrogen Phosphate Form I

A 50 ml flask was charged with 1 g of Carvedilol dihydrogen phosphateForm R and 10 ml EtOH abs. The mixture was stirred at room temperaturefor 24 hours until the crystals were converted to Form I. The crystalswere collected by filtration under reduced pressure and dried at 50° C.under reduced pressure (under 100 mmHg). The resulting solid wasanalyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.

Example 38 Preparation of Carvedilol Dihydrogen Phosphate Form L

A mixture of 4 g of Carvedilol dihydrogen phosphate in 40 ml of dioxanewas heated to reflux overnight. After cooling to room temperature, theresulting solid was filtered and dried in a vacuum oven at 45° C. togive 3.88 g of a white solid. The resulting solid was analyzed by XRDand showed Carvedilol dihydrogen phosphate Form L.

Example 39 Preparation of Carvedilol Dihydrogen Phosphate Form L

To a solution of 4 g of Carvedilol in 60 ml dioxane was slowly added0.67 ml of phosphoric acid and the resulting mixture was heated toreflux (an additional 20 ml of dioxane were added). After overnight themixture was cooled to room temperature, and stirred for overnight. Theresulting solid was filtered and dried in a vacuum oven to give 3.45 g(64.32% chemical yield) of a white solid. The resulting solid wasanalyzed by XRD to yield Carvedilol dihydrogen phosphate Form L.

Example 40 Preparation of Carvedilol Dihydrogen Phosphate Form L1

A mixture of 30 g of Carvedilol dihydrogen phosphate in 300 ml ofdioxane was heated to reflux overnight. After cooling to roomtemperature, the resulting solid was filtered and dried in a vacuum ovenat 55° C. to give 29 g of a white solid. The resulting solid wasanalyzed by XRD and showed Carvedilol dihydrogen phosphate Form L1.

Example 41 Preparation of carvedilol dihydrogen phosphate Form O

Form O was prepared by grinding about 200 mg of amorphous form with 2-3drops of water for about 1-2 min (using mortar and pestle).

Example 42 Preparation of Carvedilol Dihydrogen Phosphate Form P

A mixture of 5 g of amorphous Carvedilol dihydrogen phosphate in 50 mlof ethanol was stirred at room temperature overnight. The resultingsolid was filtered and dried in a vacuum oven at 55° C. to give 3.4 g ofa white solid. The resulting solid was analyzed by XRD and showedCarvedilol dihydrogen phosphate Form P.

Example 43 Preparation of Amorphous Carvedilol Dihydrogen Phosphate

10 g of Carvedilol dihydrogen phosphate was dissolved in 200 ml ofmethanol at reflux. The solution was sprayed (72 [ml/h]) into thechamber of a spray drying apparatus with ambient nitrogen (38 m³/h, 100°C.) at co-current flow. The atomizing flow (660[l/h]) of nitrogenproduced droplets, which led to a high evaporation rate. The temperatureof the outlet solids was 37° C. The obtained sample was analyzed by XRDand found to be amorphous.

Example 44 Preparation of Amorphous Carvedilol Dihydrogen Phosphate

10 g of carvedilol dihydrogen phosphate was dissolved in 200 ml ofacetone/water (2:1) at reflux. The solution was sprayed (72 [ml/h]) intothe chamber of a spray drying apparatus with ambient nitrogen (38 m³/h,100° C.) at co-current flow. The atomizing flow (660[l/h]) of nitrogenproduced droplets, which led to a high evaporation rate. The temperatureof the outlet solids was 33-35° C. The obtained sample was analyzed byXRD and found to be amorphous.

Example 45 Preparation of Amorphous Carvedilol Dihydrogen Phosphate

5 g of Carvedilol dihydrogen phosphate was dissolved in 100 ml ofmethanol at reflux. The solution was sprayed (72 [ml/h]) into thechamber of a spray drying apparatus with ambient nitrogen (38 m³/h, 80°C.) at co-current flow. The atomizing flow (660[l/h]) of nitrogenproduced droplets, which led to a high evaporation rate. The temperatureof the outlet solids was 19° C. The obtained sample was analyzed by XRDand found to be amorphous.

Example 46 Preparation of Amorphous Carvedilol Dihydrogen Phosphate

5 g of Carvedilol dihydrogen phosphate was dissolved in 100 ml ofmethanol. The solution was sprayed (72 [ml/h]) into the chamber of aspray drying apparatus with ambient nitrogen (38 m³/h, 100° C.) atco-current flow. The atomizing flow (660[l/h]) of nitrogen produceddroplets, which led to a high evaporation rate. The temperature of theoutlet solids was 40° C. The obtained sample was analyzed by XRD andfound to be amorphous.

Example 47 Preparation of Amorphous Carvedilol Dihydrogen Phosphate

100 g of dry Carvedilol were charged into a 5 liter stainless steel labdryer equipped with a mechanical stirrer, and a controlledheating/cooling system. 1000 ml of methanol were charged and 17 ml of85% phosphoric acid was introduced into the dryer. The agitator wasturned on, and suspension was obtained. The jacket temperature wasadjusted to 70° C. and at 58° C. clear solution was obtained. Thesolution was heated to reflux and was mixed for 15 minutes.

The solution was dried under reduced pressure (the pressure was reducedgradually from atmospheric pressure down to 40 mmHg) at 70° C. until adried product was obtained.

20 g of the product were further dried at 50° C., under reduced pressure(under 100 mmHg). 16 g of white solid were obtained. The resulting solidwas analyzed by XRD and showed Amorphous Carvedilol dihydrogenphosphate.

Example 48 Preparation of Carvedilol Dihydrogen Phosphate Form N

Carvedilol dihydrogen phosphate Form L, L1 and amorphous carvediloldihydrogen phosphate were exposed to 100% relative humidity (RH) for 7days at room temperature. According to XRD, the exposed samples arecarvedilol dihydrogen phosphate Form N.

Example 49 Preparation of a Mixture of Carvedilol Dihydrogen PhosphateForm I and Form N

100 g of dry Carvedilol were charged into a 5 liter stainless steel labdryer equipped with a mechanical stirrer and a controlledheating/cooling system. 350 ml of acetone and 150 ml of water werecharged and 17 ml of 85% phosphoric acid was introduced into the dryer.The agitator was turned on and suspension was obtained. The jackettemperature was adjusted to 70° C. and at about 60° C. a clear solutionwas obtained.

The solution was dried under reduced pressure (the pressure was reducedgradually from atmospheric pressure down to 40 mmHg) at a jacket temp of70° C. until a dried product was obtained.

The resulting solid was analyzed by XRD and showed a Carvediloldihydrogen phosphate mixture of Form I and Form N.

Example 50 Preparation of Carvedilol Dihydrogen Phosphate Form F

40 g of dry Carvedilol were charged into a 1 liter glass lab reactorequipped with a mechanical stirrer and a controlled heating/coolingsystem. 400 ml of methanol were charged. The agitator was turned on anda suspension was obtained. The temperature was adjusted to 50° C. and6.8 ml of 85% phosphoric acid was introduced into the reactor. Thesolution was heated to reflux and was mixed for 3 hours until Carvediloldihydrogen phosphate precipitated. The precipitated product was slurriedfor 1 hr and then the product was isolated by filtration under reducedpressure. The filtered cake was washed with 40 ml of methanol. 10 g ofthe wet product were dried in a tray oven at 50° C., under reducedpressure. 8 g of white solid were obtained. The resulting solid wasanalyzed by XRD and showed Carvedilol dihydrogen phosphate Form F.

Example 51 Preparation of Carvedilol Dihydrogen Phosphate Form F

20 g of dry Carvedilol base were charged into 0.5 liter glass reactorequipped with mechanical stirrer, and controlled heating/cooling system.300 ml of Methanol were charged. The agitator was turned on, thesolution was heated to 50° C. and partial dissolution was obtained, 3.4ml of 85% phosphoric acid were introduced into the reactor.

The jacket temperature was adjusted to 75° C. (at 54° C. a fulldissolution was obtained). The solution was heated and stirred for 16hours during which the product precipitated.

The product was filtered and the cake product was dried in a Vacuum ovenunder reduced pressure (under 100 mmHg) at 55° C. until a dried productwas obtained. The dry sample was analyzed by XRD and found to becarvedilol dihydrogen phosphate Form F.

Example 52 Preparation of Carvedilol Dihydrogen Phosphate Form F

A 100 ml flask was charged with Carvedilol dihydrogen phosphate Form I(2 g) and methanol (20 ml). The suspension was heated to reflux andstirred for 30 min to obtain a clear solution. The solution was furtherstirred at reflux until precipitation was observed and then cooled toroom temperature and stirred for an additional hour.

The crystals were collected by filtration under reduced pressure anddried at 50° C. under reduced pressure to obtain Carvedilol dihydrogenphosphate. (1.7 g)

The dry sample was analyzed by XRD and found to be carvedilol dihydrogenphosphate Form F.

Example 53 Preparation of Carvedilol Dihydrogen Phosphate Form F1

50 g of dry Carvedilol base were charged into 1 liter glass reactorequipped with mechanical stirrer, and controlled heating/cooling system.750 ml of EtOH abs (Ethanol absolute) were charged and 8.5 ml of 85%phosphoric acid was introduced into the reactor. The agitator was turnedon, and suspension was obtained. The jacket temperature was adjusted to80° C. The suspension was heated and stirred for 4 hours, cooled to 15°C. and stirred for 2 hours, filtered and washed with 50 ml EtOH abs.

The cake product was dried in a Vacuum oven under a reduced pressurefrom amt under 100 mmHg) at 55° C. until a dried product was obtained.

The dry sample was analyzed by XRD and found to be carvedilol dihydrogenphosphate Form F1.

Example 54 Preparation of Carvedilol Dihydrogen Phosphate Form F1

20 g of dry Carvedilol dihydrogen Phosphate Form I were charged into 1liter glass reactor equipped with mechanical stirrer, and controlledheating/cooling system.

300 ml of EtOH abs (Ethanol absolute) were charged into the reactor, Theagitator was turned on, and suspension was obtained. The jackettemperature was adjusted to 80° C. The suspension was heated and stirredfor 15.5 hours, cooled to 15° C. and stirred for 2 hours and filtered.

The cake product was dried in a vacuum oven under a reduced pressurefrom atm (under 100 mmHg) at 80° C. until a dried product was obtained.

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate Form F1.

Example 55 Preparation of Carvedilol Dihydrogen Phosphate Form F1

20 g of dry Carvedilol dihydrogen Phosphate Form R were charged into a 1liter glass reactor equipped with mechanical stirrer, and controlledheating/cooling system.

300 ml of EtOH abs (Ethanol absolute) were charged into the reactor. Theagitator was turned on, and suspension was obtained. The jackettemperature was adjusted to 80° C. The suspension was heated and stirredfor 15.5 hours, cooled to 15° C., and stirred for 2 hours and filtered.

The cake product was dried in a vacuum oven under a reduced pressurefrom atm (under 100 mmHg) at 80° C. until a dried product was obtained.

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate Form F1.

Example 56 Preparation of Carvedilol Dihydrogen Phosphate Form R

50 g of dry Carvedilol base were charged into 1 liter glass reactorequipped with mechanical stirrer, and controlled heating/cooling system.750 ml of IPA (isopropyl alcohol) were charged and 8.5 ml of 85%phosphoric acid was introduced into the reactor. The agitator was turnedon, and suspension was obtained. The jacket temperature was adjusted to25° C. The suspension was stirred for 4 hours at 25° C., cooled to 15°C., stirred for 2 hours, filtered and washed with 50 ml IPA.

The cake product was dried in a Vacuum oven under a reduced pressurefrom (under 100 mmHg) at 55° C. until a dried product was obtained.

The dry sample was analyzed by XRD and found to be carvedilol dihydrogenphosphate Form R.

Example 57 Preparation of Carvedilol Dihydrogen Phosphate Form R

50 g of dry Carvedilol base were charged into 1 liter glass reactorequipped with mechanical stirrer, and controlled heating/cooling system.250 ml of IPA (isopropyl alcohol) were charged and 8.5 ml of 85%phosphoric acid was introduced into the reactor. The agitator was turnedon, and suspension was obtained. The jacket temperature was adjusted to52.5° C. The suspension was heated and stirred for 2 hours, cooled to15° C., stirred for 2 hours, filtered and washed with 50 ml IPA.

The cake product was dried in a Vacuum oven under a reduced pressurefrom (under 100 mmHg) at 55° C. until a dried product was obtained.

The dry sample was analyzed by XRD and found to be carvedilol dihydrogenphosphate Form R including traces of Form I.

Example 58 Preparation of Carvedilol Dihydrogen Phosphate Form R

A 50 ml flask was charged with 1 g of Carvedilol dihydrogen phosphateamorphous and 10 ml IPA. The mixture was stirred at room temperature for24 hours until the crystals were converted to Form R. The crystals werecollected by filtration under reduced pressure and dried at 50° C. underreduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate Form R.

Example 59 Preparation of Carvedilol Dihydrogen Phosphate Form R

A 50 ml flask was charged with 1 g of Carvedilol dihydrogen phosphateForm F1 and 10 ml IPA. The mixture was stirred at room temperature for24 hours until the crystals were converted to Form R. The crystals werecollected by filtration under reduced pressure and dried at 50° C. underreduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate Form R.

Example 60 Preparation of Carvedilol Dihydrogen Phosphate Form Y

450 g of dry Carvedilol were charged into a 10 liter glass reactorequipped with mechanical stirrer, and controlled heating/cooling system.6,750 ml of EtOH abs (Ethanol absolute) were charged and 768.5 ml of 85%phosphoric acid was introduced into the reactor. The agitator was turnedon and suspension was obtained. The jacket temperature was adjusted to80° C. The suspension was heated and stirred. A sample from thesuspension was taken after 3 hours and then was filtered.

The wet sample was analyzed by XRD and found to be carvedilol dihydrogenphosphate Form Y.

Examples to Obtain Essentially Form I Example 61

Carvedilol dihydrogen phosphate Form F was exposed to 100% relativehumidity (RH) for 7 days at 60° C. According to XRD, the resultingexposed sample is carvedilol dihydrogen phosphate Form I.

Example 62

Carvedilol dihydrogen phosphate Form N was placed in oven at atemperature of 120° C. for 30 min. The resulting solid was analyzed byXRD and showed a Carvedilol dihydrogen phosphate Form I.

Example 63

A 50 ml flask is charged with 1 gr of Carvedilol dihydrogen phosphateForm F1 and 10 ml Acetone. The mixture is stirred at room temperaturefor 1 day while which the crystals are converted to Form I. The crystalsare collected by filtration under reduced pressure and dried at 80° C.under reduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate FORM I.

Example 64

A 50 ml flask is charged with 1 gr of Amorphous Carvedilol dihydrogenphosphate and 10 ml Acetone. The mixture is stirred at room temperaturefor 1 day until the crystals are converted to Form I. The crystals arecollected by filtration under reduced pressure and dried at 80° C. underreduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate Form I.

Example 65

A 50 ml flask is charged with 1 gr of Carvedilol dihydrogen phosphateForm R and 10 ml Acetone. The mixture is stirred at room temperature for1 day until the crystals are converted to Form I. The crystals arecollected by filtration under reduced pressure and dried at 80° C. underreduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate FORM I.

Example 66

A 100 ml flask is charged with 7 gr of Carvedilol dihydrogen phosphateForm N and 70 ml Acetone. The mixture is stirred at room temperature for1 day while which the crystals are converted to Form I. The crystals arecollected by filtration under reduced pressure and dried at 50° C. underreduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate FORM I.

Example 67

Carvedilol dihydrogen phosphate Form L1 was placed in oven at atemperature of about between 80-120° C. for 30 min. The resulting solidwas analyzed by XRD and showed a Carvedilol dihydrogen phosphate Form I.

Example 68

Amorphous Carvedilol dihydrogen phosphate was placed in oven at atemperature of 120° C. for 30 min. The resulting solid was analyzed byXRD and showed a Carvedilol dihydrogen phosphate Form I.

Example 69

40 ml of water was added to 4 gr Carvedilol dihydrogen phosphate Form I(MAB-1449). The mixture was slurred at room temperature over night.

The suspension was vacuum filtered and dried in vacuum at 50° C. in ovenover night to obtain 3.13 gr (78% yield). The resulting solid wasanalyzed by XRD and showed a mixture of carvedilol dihydrogen phosphateForm I and carvedilol hydrogen phosphate Form G.

Example 70

Carvedilol dihydrogen phosphate Form P was placed in oven at atemperature of about between 80-120° C. for about 30 min. The resultingsolid was analyzed by XRD and showed a Carvedilol dihydrogen phosphateForm I.

Example 71

Carvedilol dihydrogen phosphate Form R was placed in oven at atemperature of about 120° C. for about 30 min. The resulting solid wasanalyzed by XRD and showed a Carvedilol dihydrogen phosphate Form I.

Example 72

Carvedilol dihydrogen phosphate Form N was pressed by pressure of 2 tonby a laboratory press for about 1 min. The resulting solid was analyzedby XRD and showed a Carvedilol dihydrogen phosphate mixture of Form Nand Form I.

Example 73

Carvedilol dihydrogen phosphate Form P was pressed by pressure of 2 tonby a laboratory press for about 1 min. The resulting solid was analyzedby XRD and showed a Carvedilol dihydrogen phosphate Form I.

Example 74

Carvedilol dihydrogen phosphate Form P was ground by mortal and pestlefor about 1 min. The resulting solid was analyzed by XRD and showed aCarvedilol dihydrogen phosphate Form I.

Example 75

Carvedilol dihydrogen phosphate Form F was ground by mortal and pestlewith 2-3 drops of butanol for about 1 min. The resulting solid wasanalyzed by XRD and showed a Carvedilol dihydrogen phosphate mixture ofForm F and Form I.

Example 76

Amorphous Carvedilol dihydrogen phosphate was placed in an atmosphere ofthe following solvents for 7 days: n-propanol, iso-propanol, butanol,acetone and ethyl acetate. The resulting solids were analyzed by XRD andshowed a Carvedilol dihydrogen phosphate mixture of amorphous form andForm I for n-propanol, iso-propanol, butanol, acetone and ethyl acetate.

Example 77

A 50 ml flask is charged with 0.6 gr of Carvedilol dihydrogen phosphateForm N and 6 ml water. The mixture is stirred at room temperature for 3days until part of the crystals are converted to Form I. The crystalsare collected by filtration under reduced pressure and dried at 50° C.under reduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed a mixture ofCarvedilol dihydrogen phosphate FORM N and Form I.

Examples to Obtain Essentially Amorphous Form (1:1) Example 78

Carvedilol dihydrogen phosphate Form F was placed in oven at atemperature of about 140° C. for about 30 min. The resulting solid wasanalyzed by XRD and showed an amorphous form of Carvedilol dihydrogenphosphate.

Example 79

Carvedilol dihydrogen phosphate Form R was placed in oven at atemperature of about 100° C. for about 30 min. The resulting solid wasanalyzed by XRD and showed a mixture of Carvedilol dihydrogen phosphateForm R and amorphous form.

Example 80

Solid pharmaceutical compositions of amorphous form and the followingexcipients: lactose monohydrate, sucrose and avicel were compacted intoa dosage form like a tablet.

Examples to Obtain Form N (1:1) Example 81

Carvedilol dihydrogen phosphate Form F1 was exposed to 100% relativehumidity (RH) for 7 days at room temperature. The resulting solid wasanalyzed by XRD and showed a Carvedilol dihydrogen phosphate mixture ofForm N and Form F1.

Example 82

Carvedilol dihydrogen phosphate Form R was exposed to 100% relativehumidity (RH) for 7 days at room temperature. According to XRD, theexposed sample is Carvedilol dihydrogen phosphate Form N.

Example 83

Carvedilol dihydrogen phosphate Form F1 was exposed to 100% relativehumidity (RH) for 7 days at room temperature. The resulting solid wasanalyzed by XRD and showed a Carvedilol dihydrogen phosphate mixture ofForm F1 and Form N.

Example 84

Carvedilol dihydrogen phosphate Form N was placed in oven at atemperature of 80° C. for 30 min. The resulting solid was analyzed byXRD and showed a Carvedilol dihydrogen phosphate mixture of amorphousform and Form N.

Example 85

Solid pharmaceutical compositions of Form N and the followingexcipients: lactose monohydrate, sucrose and avicel were compacted intoa dosage form like a tablet.

Examples to Obtain Form F1 (1:1) Example 86

A 50 ml flask is charged with 0.6 gr of Carvedilol dihydrogen phosphateForm N and 6 ml EtOH. The mixture is stirred at room temperature for 3days until the crystals are converted to Form F1. The crystals arecollected by filtration under reduced pressure and dried at 50° C. underreduced pressure (under 100 mmHg).

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate FORM F1.

Example 87

30 gr (on dry basis) of wet Carvedilol base were charged into 1 literglass reactor equipped with mechanical stirrer, and controlledheating/cooling system. 810 ml of EtOH abs (Ethanol absolute) werecharged, the agitator was turned on and the reactor content was heatedto reflux (78-82° C.), during the heating full dissolution was achieved.

5.6 ml of 85% phosphoric acid and 90 ml of EtOH abs. were introducedinto the reactor. Seeding was preformed with 0.15 gr Carvediloldihydrogen phosphate FORM F1 slurried in 8 ml EtOH abs. The reactorcontent was stirred for 4 hr, cooled to 15° C. stirred for another 2 hr,filtered and washed with 60 ml ETOH abs.

The cake product was dried in a vacuum oven under a reduced pressure(under 100 mmHg) at 50° C. until a dried product was obtained.

The resulting solid was analyzed by XRD and showed Carvedilol dihydrogenphosphate Carvedilol dihydrogen phosphate FORM F1.

Example 88

Solid pharmaceutical compositions of Form F1 and the followingexcipients: lactose monohydrate, sucrose and avicel were compacted intoa dosage form like a tablet.

Examples to Obtain Form R (1:1) Example 89

A 50 ml flask is charged with 0.6 gr of Carvedilol dihydrogen phosphateForm N and 6 ml IPA. The mixture is stirred at room temperature for 3days while which the crystals are converted to Form R. The crystals arecollected by filtration under reduced pressure and dried at 50° C. underreduced pressure (under 100 mmHg). The resulting solid was analyzed byXRD and showed Carvedilol dihydrogen phosphate FORM R.

Example 90

Solid pharmaceutical compositions of Form R and the followingexcipients: lactose monohydrate, sucrose and avicel were compacted intoa dosage form like a tablet.

Example 91 Process for the Preparation of Carvedilol DihydrogenPhosphate Form F2

Carvedilol dihydrogen phosphate Form I was used for crystallization.Sample (40 mg) was dissolved in ethanol (4 ml, Merck 1.11727.2500) at70° C. The flask was placed at the thermos flask at 50° C. and wasallowed to cool slowly to 20° C. within 6 days. Data collection waspreformed at 150 K.

Process for the Preparation of Form Q Example 92

Carvedilol hydrogen phosphate Form K was exposed to 0% relative humidity(RH) for 7 days at room temperature. The resulting solid was analyzed byXRD and showed Form Q content.

Example 93 Process for the Preparation of Carvedilol Phosphate SaltPhosphate Form W

Carvedilol dihydrogen phosphate form F1, sample LL-11193, was added to30 ml of 0.1 M KH₂PO₄ (pH=7.0 adjusted with 1M KOH) until a suspensionwas obtained. The suspension was stirred at was stirred at 25° C. for 24hr and filtered under vacuum. XRD analysis showed that it was a newcrystal form (designated Form W).

1-24. (canceled)
 25. Essentially amorphous carvedilol dihydrogen phosphate containing not less than about 50% by weight of amorphous carvedilol dihydrogen phosphate.
 26. The essentially amorphous carvedilol dihydrogen phosphate of claim 25 characterized by data selected from the group consisting of: (a) a solid-state ¹³C-NMR spectrum having broad chemical shift resonances at about 154.6, 146.7 and 140.3±0.2 ppm; and (b) a solid-state ¹³C-NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.2, 46.3 and 39.9±0.1 ppm; and (c) a solid-state ¹³C-NMR spectrum having broad chemical shift resonances at about 154.6, 146.7, 140.3 and 100.4±0.2 ppm.
 27. The essentially amorphous carvedilol dihydrogen phosphate of claim 26 further characterized by data selected from the group consisting of: a solid-state ¹³C-NMR spectrum having chemical shift resonances, which are broader than chemical shift resonances of a crystalline material, at about 121.9 and 111.5±0.2 ppm; and a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 21.5 and 11.1±0.1 ppm.
 28. The essentially amorphous carvedilol dihydrogen phosphate of claim 25 comprising less than about 50% crystalline carvedilol or crystalline carvedilol phosphate salt by weight.
 29. The essentially amorphous carvedilol dihydrogen phosphate of claim 25 comprising less than about 50% crystalline carvedilol dihydrogen phosphate Form I by weight.
 30. Pure amorphous carvedilol dihydrogen phosphate containing not less than about 80% by weight of amorphous carvedilol dihydrogen phosphate.
 31. A process for preparing the essentially amorphous carvedilol dihydrogen phosphate comprising dissolving carvedilol dihydrogen phosphate in a solvent selected from the group consisting of C₁-C₈ alcohols and mixtures of C₃₋₇ ketones with water, followed by solvent removal.
 32. The process of claim 31 where the solvent is removed by fast evaporation.
 33. The process of claim 31 where the solvent is removed by drying under a pressure of less than one atmosphere or spray drying.
 34. The process of claim 31 where carvedilol dihydrogen phosphate is dissolved in acetone and the ratio of acetone/water is about 2:1 (v/v) and the solvent is removed by spray drying.
 35. The process of claim 31 where the solvent is removed by spray drying and the spray drying is carried out with an inlet temperature of above about 80° C. to about 160° C. and an outlet temperature of about 30° C. to about 110° C.
 36. A crystalline form carvedilol dihydrogen phosphate (Form N) characterized by data selected from the group consisting of: (a) X-ray powder diffraction reflections at about: 6.0, 6.9, 15.2, 16.3 and 17.4 degrees two theta ±0.2 degrees two theta; (b) X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7 15.2 and 18.1 degrees two theta ±0.2 degrees two theta; (c) X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7, 15.2 and 17.4±0.2 degrees two theta ±0.2 degrees two theta; (d) a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 154.4, 146.9, 138.4, and 110.9±0.2 ppm; (e) a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9, 45.4, 36.9, and 9.4±0.1 ppm; (f) a solid-state ¹³C-NMR spectrum substantially as depicted in FIG. 6 or 6 a; and (g) an X-ray powder diffraction pattern substantially as depicted in FIG. 4 or FIG.
 5. 37. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 characterized by X-ray powder diffraction reflections at about: 6.0, 6.9, 15.2, 16.3 and 17.4 degrees two theta ±0.2 degrees two theta.
 38. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 37 further characterized by X-ray powder diffraction reflections at about 18.1, 20.6, 24.6 and 26.3 degrees two-theta, ±0.2 degrees two-theta.
 39. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 characterized by a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 154.4, 146.9 and 138.4±0.2 ppm.
 40. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 39 further characterized by a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 141.3, and 122.0±0.2 ppm.
 41. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 characterized by a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9, 45.4 and 36.9±0.1 ppm.
 42. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 41 further characterized by a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 39.8, and 20.5±0.1 ppm.
 43. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 characterized by a solid-state ¹³C NMR spectrum substantially as depicted in FIG. 6 or 6 a.
 44. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 4 or FIG.
 5. 45. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 containing less than about 25% by weight of amorphous forms of carvedilol and carvedilol phosphate salts or other crystalline forms of carvedilol and carvedilol phosphate salts.
 46. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 containing less than about 25% by weight of crystalline carvedilol dihydrogen phosphate Form I.
 47. A process for preparing carvedilol dihydrogen phosphate (Form N) characterized by data selected from the group consisting of: (a) X-ray powder diffraction reflections at about: 6.0, 6.9, 15.2, 16.3 and 17.4 degrees two theta ±0.2 degrees two theta; (b) X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7 15.2 and 18.1 degrees two theta ±0.2 degrees two theta; (c) X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7, 15.2 and 17.4±0.2 degrees two theta ±0.2 degrees two theta; (d) a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 154.4, 146.9, 138.4, and 110.9±0.2 ppm; (e) a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9, 45.4, 36.9, and 9.4±0.1 ppm; (f) a solid-state ¹³C-NMR spectrum substantially as depicted in FIG. 6 or 6 a; and (g) an X-ray powder diffraction pattern substantially as depicted in FIG. 4 or FIG. 5; comprising exposing carvedilol dihydrogen phosphate Form L, carvedilol dihydrogen phosphate Form L1, or amorphous carvedilol dihydrogen phosphate to relative humidity of greater than about 80%.
 48. The process of claim 47 where the carvedilol dihydrogen phosphate Form L, carvedilol dihydrogen phosphate Form L1, or amorphous carvedilol dihydrogen phosphate is exposed to relative humidity of greater than about 80% preferably for at least about 7 days.
 49. A process for preparing the carvedilol dihydrogen phosphate (Form N) characterized by data selected from the group consisting of: (a) X-ray powder diffraction reflections at about: 6.0, 6.9, 15.2, 16.3 and 17.4 degrees two theta ±0.2 degrees two theta; (b) X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7 15.2 and 18.1 degrees two theta ±0.2 degrees two theta; (c) X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7, 15.2 and 17.4±0.2 degrees two theta ±0.2 degrees two theta; (d) a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 154.4, 146.9, 138.4, and 110.9±0.2 ppm; (e) a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9, 45.4, 36.9, and 9.4±0.1 ppm; (f) a solid-state ¹³C-NMR spectrum substantially as depicted in FIG. 6 or 6 a; and (g) an X-ray powder diffraction pattern substantially as depicted in FIG. 4 or FIG. 5; comprising drying carvedilol dihydrogen phosphate Form O.
 50. The process of claim 49 where carvedilol dihydrogen phosphate Form O is heated to a temperature of from about 30° C. to about 70° C. to obtain carvedilol dihydrogen phosphate Form N.
 51. A crystalline form of carvedilol dihydrogen phosphate (Form F1) characterized by data selected from the group consisting of: (a) X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 21.2 and 25.0 degrees two theta ±0.2 degrees two theta; (b) any five peaks selected from the following list of PXRD peaks at about: 7.6, 8.5, 9.8, 10.9, 12.0, 13.3, 15.2 and 16.9±0.2 degrees two theta; (c) X-ray powder diffraction reflections at about: 7.6, 10.9, 13.3, 15.2 and 18.8 degrees two theta ±0.2 degrees two theta; d) X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 15.2 and 16.9±0.2 degrees two theta; (e) X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 14.7, 15.2 and 22.8±0.2 degrees two theta; (f) X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 13.3 and 15.2±0.2 degrees two theta; (g) a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 155.3, 145.3 and 127.7±0.2 ppm; (h) a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.6, 42.6 and 25±0.1 ppm; (i) an X-ray powder diffraction pattern substantially as depicted in FIG. 26 or FIG. 27; and (j) a solid-state ¹³C NMR spectrum substantially as depicted in FIG. 28 or 28 a.
 52. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 21.2 and 25.0 degrees two theta ±0.2 degrees two theta.
 53. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by any five peaks selected from the following list of PXRD peaks at about: 7.6, 8.5, 9.8, 10.9, 12.0, 13.3, 15.2 and 16.9±0.2 degrees two theta.
 54. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by X-ray powder diffraction reflections at about: 7.6, 10.9, 13.3, 15.2 and 18.8 degrees two theta ±0.2 degrees two theta.
 55. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 15.2 and 16.9±0.2 degrees two theta.
 56. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 14.7, 15.2 and 22.8±0.2 degrees two theta.
 57. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 13.3 and 15.2±0.2 degrees two theta.
 58. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 155.3, 145.3 and 127.7±0.2 ppm.
 59. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.6, 42.6 and 25±0.1 ppm.
 60. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 26 or FIG.
 27. 61. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 characterized by a solid-state ¹³C NMR spectrum substantially as depicted in FIG. 28 or 28 a.
 62. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 containing less than about 20% by weight of other crystalline forms of carvedilol and carvedilol phosphate salts.
 63. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51 containing less than about 20% by weight of crystalline carvedilol dihydrogen phosphate Form I.
 64. Crystalline carvedilol dihydrogen phosphate Form F1 ethanol solvate.
 65. The crystalline carvedilol dihydrogen phosphate Form F1 of claim 64 that is a hemiethanol solvate.
 66. A process for preparing carvedilol dihydrogen phosphate (Form F1) characterized by data selected from the group consisting of: (a) X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 21.2 and 25.0 degrees two theta ±0.2 degrees two theta; (b) any five peaks selected from the following list of PXRD peaks at about: 7.6, 8.5, 9.8, 10.9, 12.0, 13.3, 15.2 and 16.9±0.2 degrees two theta; (c) X-ray powder diffraction reflections at about: 7.6, 10.9, 13.3, 15.2 and 18.8 degrees two theta ±0.2 degrees two theta; d) X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 15.2 and 16.9±0.2 degrees two theta; (e) X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 14.7, 15.2 and 22.8±0.2 degrees two theta; (f) X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 13.3 and 15.2±0.2 degrees two theta; (g) a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 155.3, 145.3 and 127.7±0.2 ppm; (h) a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.6, 42.6 and 25±0.1 ppm; (i) an X-ray powder diffraction pattern substantially as depicted in FIG. 26 or FIG. 27; and (i) a solid-state ¹³C NMR spectrum substantially as depicted in FIG. 28 or FIG. 28 a; comprising combining carvedilol dihydrogen phosphate and ethanol to obtain a slurry; and maintaining the slurry for at least about 4 hours to obtain the crystal form.
 67. The process of claim 66 where carvedilol and phosphoric acid are present in a molar ratio of about 0.8:1 to about 1.2:1.
 68. The process of claim 66 where absolute ethanol is used.
 69. The process of claim 66 where the carvedilol, phosphoric acid and ethanol are heated to reflux.
 70. The process of claim 69 where cooling is used to induce precipitation of the carvedilol dihydrogen phosphate.
 71. The process of claim 66 where the carvedilol that is combined with ethanol is carvedilol dihydrogen phosphate in any crystalline form.
 72. The process of claim 66 where the carvedilol that is combined with ethanol is carvedilol dihydrogen phosphate Form I or Form R. 73-161. (canceled)
 162. A pharmaceutical composition comprising the crystalline or amorphous form of any one of claims 25, 36, or 51 and at least one pharmaceutically acceptable excipient.
 163. A method of treating a mammal suffering from congestive heart failure or management of hypertension comprising administering a pharmaceutical composition comprising: (i) essentially amorphous carvedilol dihydrogen phosphate; (ii) pure amorphous carvedilol dihydrogen phosphate; (iii) a crystalline form carvedilol dihydrogen phosphate (Form N) characterized by data selected from the group consisting of: (a) X-ray powder diffraction reflections at about: 6.0, 6.9, 15.2, 16.3 and 17.4 degrees two theta ±0.2 degrees two theta; (b) X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7 15.2 and 18.1 degrees two theta ±0.2 degrees two theta; (c) X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7, 15.2 and 17.4±0.2 degrees two theta ±0.2 degrees two theta; (d) a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 154.4, 146.9, 138.4, and 110.9±0.2 ppm; (e) a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9, 45.4, 36.9, and 9.4±0.1 ppm; (f) a solid-state ¹³C-NMR spectrum substantially as depicted in FIG. 6; and (g) an X-ray powder diffraction pattern substantially as depicted in FIG. 4 or FIG. 5; or (iv) a crystalline form of carvedilol dihydrogen phosphate (Form F1) characterized by data selected from the group consisting of: (a) X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 21.2 and 25.0 degrees two theta ±0.2 degrees two theta; (b) any five peaks selected from the following list of PXRD peaks at about: 7.6, 8.5, 9.8, 10.9, 12.0, 13.3, 15.2 and 16.9±0.2 degrees two theta; (c) X-ray powder diffraction reflections at about: 7.6, 10.9, 13.3, 15.2 and 18.8 degrees two theta ±0.2 degrees two theta; d) X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 15.2 and 16.9±0.2 degrees two theta; (e) X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 14.7, 15.2 and 22.8±0.2 degrees two theta; (f) X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 13.3 and 15.2±0.2 degrees two theta; (g) a solid-state ¹³C-NMR spectrum having chemical shift resonances at about 155.3, 145.3 and 127.7±0.2 ppm; (h) a solid-state ¹³C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.6, 42.6 and 25±0.1 ppm; (i) an X-ray powder diffraction pattern substantially as depicted in FIG. 27, FIG. 28, or FIG. 38; and (j) a solid-state ¹³C NMR spectrum substantially as depicted in FIG. 29, FIG. 29 a, or FIG. 39; and at least one pharmaceutically acceptable excipient to the mammal. 164-192. (canceled)
 193. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 that is a dihydrate.
 194. The pure amorphous carvedilol dihydrogen phosphate of claim 30 comprising less than about 20% crystalline carvedilol or crystalline carvedilol phosphate salt by weight.
 195. The pure amorphous carvedilol dihydrogen phosphate of claim 30 comprising less than about 20% crystalline carvedilol dihydrogen phosphate Form I by weight.
 196. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 characterized by X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7 15.2 and 18.1 degrees two theta ±0.2 degrees two theta.
 197. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 characterized by X-ray powder diffraction reflections at about: 6.0, 6.9, 13.7, 15.2 and 17.4 degrees two theta ±0.2 degrees two theta.
 198. The essentially amorphous carvedilol dihydrogen phosphate of claim 28 comprising less than about 20% crystalline carvedilol or crystalline carvedilol phosphate salt by weight.
 199. The essentially amorphous carvedilol dihydrogen phosphate of claim 198 comprising less than about 10% crystalline carvedilol or crystalline carvedilol phosphate salt by weight.
 200. The essentially amorphous carvedilol dihydrogen phosphate of claim 199 comprising less than about 5% crystalline carvedilol or crystalline carvedilol phosphate salt by weight.
 201. The essentially amorphous carvedilol dihydrogen phosphate of claim 200 comprising less than about 1% crystalline carvedilol or crystalline carvedilol phosphate salt by weight.
 202. The essentially amorphous carvedilol dihydrogen phosphate of claim 29 comprising less than about 20% crystalline carvedilol dihydrogen phosphate Form I by weight.
 203. The essentially amorphous carvedilol dihydrogen phosphate of claim 202 comprising less than about 10% crystalline carvedilol dihydrogen phosphate Form I by weight.
 204. The essentially amorphous carvedilol dihydrogen phosphate of claim 203 comprising less than about 5% crystalline carvedilol dihydrogen phosphate Form I by weight.
 205. The essentially amorphous carvedilol dihydrogen phosphate of claim 204 comprising less than about 1% crystalline carvedilol dihydrogen phosphate Form I by weight.
 206. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 45 containing less than about 10% by weight of amorphous forms of carvedilol and carvedilol phosphate salts or other crystalline forms of carvedilol and carvedilol phosphate salts.
 207. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 206 containing less than about 5% by weight of amorphous forms of carvedilol and carvedilol phosphate salts or other crystalline forms of carvedilol and carvedilol phosphate salts.
 208. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 207 containing less than about 1% by weight of amorphous forms of carvedilol and carvedilol phosphate salts or other crystalline forms of carvedilol and carvedilol phosphate salts.
 209. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 46 containing less than about 10% by weight of crystalline carvedilol dihydrogen phosphate Form I.
 210. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 209 containing less than about 5% by weight of crystalline carvedilol dihydrogen phosphate Form I.
 211. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 210 containing less than about 1% by weight of crystalline carvedilol dihydrogen phosphate Form I.
 212. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 62 containing less than about 10% by weight of other crystalline forms of carvedilol and carvedilol phosphate salts.
 213. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 212 containing less than about 5% by weight of other crystalline forms of carvedilol and carvedilol phosphate salts.
 214. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 213 containing less than about 1% by weight of other crystalline forms of carvedilol and carvedilol phosphate salts.
 215. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 63 containing less than about 10% by weight of crystalline carvedilol dihydrogen phosphate Form I.
 216. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 215 containing less than about 5% by weight of crystalline carvedilol dihydrogen phosphate Form I.
 217. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 216 containing less than about 1% by weight of crystalline carvedilol dihydrogen phosphate Form I.
 218. The pure amorphous carvedilol dihydrogen phosphate of claim 194 comprising less than about 10% crystalline carvedilol or crystalline carvedilol phosphate salt by weight.
 219. The pure amorphous carvedilol dihydrogen phosphate of claim 218 comprising less than about 5% crystalline carvedilol or crystalline carvedilol phosphate salt by weight.
 220. The pure amorphous carvedilol dihydrogen phosphate of claim 219 comprising less than about 1% crystalline carvedilol or crystalline carvedilol phosphate salt by weight.
 221. The pure amorphous carvedilol dihydrogen phosphate of claim 195 comprising less than about 10% crystalline carvedilol dihydrogen phosphate Form I by weight.
 222. The pure amorphous carvedilol dihydrogen phosphate of claim 221 comprising less than about 5% crystalline carvedilol dihydrogen phosphate Form I by weight.
 223. The pure amorphous carvedilol dihydrogen phosphate of claim 222 comprising less than about 1% crystalline carvedilol dihydrogen phosphate Form I by weight. 